Topical Drug Delivery 1-7 Flashcards
State the functions of the skin
- Largely they act as a protective barrier against external forces; protects against loss of moisture, microbial infection etc.
- Stabilises blood pressure and temperature (site of heat loss for the body)
- Mediates sensitisation of
- Temperature, touch and pain
State the three main layers of the skin
Epidermis - Dermis - Subcutaneous tissue
What is the hypodermis, What are its thickness factors dependent on?
The hypodermis (the subcutaneous tissue) is a structured fatty layer that exists almost over the whole body. The purpose of this layer is partially to provide protection to the body and also serves as a source of energy
Thickness depends on:
- Sex
- Age
- Endocrine and nutritional status of the person
Describe the dermis
Composed of a matrix of connective tissue, formed of fibrous protein (around 80% collagen and elastin) and also glycosaminoglycan gel (20%), As this is a relatively hydrophilic layer, this is a potential barrier to the absorption of some lipophilic molecules.
It is the site of:
- Blood vessels
- Some Sweat glands
- Hair follicles
What sweat glands are found in the dermis
Eccrine sweat glands
Apocrine sweat glands
Sebacious glands
What does the Eccrine glands secrete?
- These glands secrete a watery fluid with a pH of 4-7 and can secrete roughly 1L per day of fluid.
What do Apocrine glands release?
The apocrine sweat glands secrete a different fluid; milky fluid in nature and is responsible for the “sweat odour”.
Talk to me about the sebaceuous gland
Found around Forehead/face/ear and Middle of the back. Releases Sebum. The sebaceous glands are the site at which acne generally develops. This could potentially be a site for drug delivery into the skin for treating acne conditions. Sebum is a complex mixture of lipids of which lubricate the skin surface and maintains the skin at pH around 5
What is the epidermis?
It’s the top layer of the skin - A major barrier to drug absorption through the skin.
- This thickness of this layer varies depending on the site on the body:
- 0.06mm(eyelids) – 0.8mm(soles of feet)
formed of four distinct layers, and by the time we get to the top layer of the skin, the cells found on the stratum corneum become non-viable/dead cells by the time they are at the top of the skin surface.
Describe the basement membrane
Found at the very base of the stratum corneum. The basement membrane is connected to the rest of the epidermis via hemi-desmosomes. Above the basement membrane is the viable epidermis
describe the viable epidermis
- Formed of: 75-50µm thick, stratified, squamous epithelium; a major component of the stratum corneum being the keratinocytes.
- There are four distinctive strata of which are responsible for keratinocyte differentiation; keratinocytes differentiate as they move up this epidermis layer until they reach the stratum corneum, at which we have non-viable cells.
Name the last of the 4 strata, and explain what is it composed of
stratum basale (just above BM). Consists of 4 viable, active dividing cells
- Keratinocytes - the dominant cell type in the skin structure. At this point, its a viable cell. Later migrates upwards
- Melanocytes (synthesis of melanin free radical scavengers and absorb UV radiation),
- Langerhans cells, capable of antigen binding. So plays an immune role to alert body of foreign species
- Merkel cells involved with skin sensation because associated with nerve endings
Describe the stratum corneum!
(“Horny layer” - Uppermost layer)
This layer forms the main barrier to absorption through the skin; the part of the skin of which is mainly responsible for its barrier properties.
- It is this layer of the skin which prevents water loss or terrestrial animals as well as preventing entry of microorganisms/dirt into the skin.
- Formed of 10µm layer of thick, dead, flattened keratinocytes
In this layer, once the keratinocytes have differentiated up to the upper layer and become fully flattened, with their contents fully extruded – we refer to them as corneocytes. These are very dry cells of which have very low water content compared to other areas of the body
Talk about the Stratum Corneum on a cellular level
- Dead, flattened cells with insoluble keratin bundles in them.
- The intracellular region between the flattened corneocytes is formed of a lipid domain (formed of mostly lipid and some desmosomes which aid cohesion between corneocytes)
what distinguishing feature makes the stratum corneum impenetratable
In terms of a drug passing through the skin it is not as simple as a lipophilic drug being able to cross through three lipidic domains. It will have to move through structured rigid layers of lipids, providing three different layers of differing hydrophobicity. This is the main reason of which the stratum corneum is a principle barrier to penetration and thus drug delivery.
summarise the regions drug penetrate the skin through
what is able to permeate through all levels of skin?
nicotine patch, hormones, fentanyl etc. Able to permeate through all layers of the skin and successfully reach the blood.
Appendages (hair follicles + sweat glands) are sites of delivery for what drugs?
antimicrobials, depilatories, acne treatment/infection of the follicle
what kind of drugs exhibit a local effect?
corticosteroids, cytotoxics, antiviral, antihistamines, anaesthetics (interested in permeating through one layer) – They’re not systemic
What type of drugs are targeted at the Stratum Corneum?
Barriers/repellants, sunscreens, antimicrobials for infections on the surface of skin, antiseptics (e.g. targeting wounds)
For drugs to be delivered successfully to the skin, they need…
Low molecular weight: <500 Da
LogP (octanol/water partition coefficient): 1-3
Low melting point <200˚C
Relatively high solubility
(Need high concentration of drug to maintain the concentration gradient)
>1mg/mL
In order to create a diffusion gradient to encourage transport of the drug through the skin (through this impermeable barrier – the creation of a concentration gradient is extremely important as a driving force to get drugs into the skin)
Advantages of drug delivery to the skin:
- It is a non-invasive dosing mechanism
- Unlike oral dosage forms we can bypass the GI tract and first-pass metabolism
- Allows lower drug doses for topical delivery as we are targeting our site of action
- Minimises any side effects that may occur from systemic administration
- Easy, simple to apply – increase patient compliance, preferred over routes such as injection
- Dosing regimen can easily and promptly be interrupted – we can easily instantly stop the delivery of the drug to the patient if needed
- This type of drug delivery is flexible and versatile – there is a possibility of use as controlled/sustained systemic (e.g. transdermal patches) or localised (dermal) drug delivery.
State the three mechanisms of drug transport to the skin
Shunt (transappendageal) route
Paracellular route
Transcellular route (intracellular)
With the transcellular route, drugs must be able to..
For this route, the drug is going to diffuse through, into the keratinised cell and then diffuse back out again going through the cell layer – in and out of the cells one by one.
Whats special about the Transappendageal route, and what drug properties must be like?
This route provides a direct route into the dermis, bypassing the stratum corneum
water soluble molecules that they may have relatively high diffusion coefficient for passing through this route into the lower layers of the skin.
With the paracellular (intercellular) route - how does the drug move?
Is it a simple route?
- Around the outside of the keratinised cells (through the lipid matrix that is surrounding these flattened cells).
- This is not a simple passage through one lipid phase – this is a highly torturous multiple structure layer. The drug needs to pass between different lipid layers through the structure and this may retard the passage through this layer.
Whhat route is the shortest path length?
Transcellular, as it travelling directly through the stratum corneum and so it has a higher rate of mass transfer through the skin.
Patient factors affecting drug transport across the skin:
- Affected by hydration of the skin (the transcellular route; travelling through the cells is going to be more challenging if we have dehydrated skin as we are relying on this hydration to help the diffusion of drugs through the skin layer)
- Presence of hair follicles – going to have an effect on the transappendageal route
-
Age of patient
- Hydration and blood flow to the skin decreases with age – need to create a diffusion gradient which powers mass transport across the skin
- Anatomical site of skin (varied thickness)
what three things does our formulation need to do effectively?
- Need to ensure that our drug is effectively released from formulation – this is important as we need to maintain a high diffusion coefficient as the driving force for transdermal and topical drug delivery.
- Need to ensure that the drug can penetrate into the skin to the site of action
- Need to tell that the drug is able to activate a pharmacological response – needs to remain stable, cannot be metabolically damaged during its delivery
Explain this: (fick’s law of diffusion)
J= flux of permeant
D= Diffusion coefficient
Dc/dx = concentration gradient
The minus sign tells us that the diffusion is going down a concentration gradient (from high concentration to low concentration). Diffusion coefficient is inversely proportional to the molecular weight/size and viscosity; smaller compound = the greater the diffusion coefficient + greater rate of mass transfer per unit of time.
How do we express and relate parition coefficient, Diffusion coefficient and thickeness of the skin?
.
Two things particularly crucial for drug delivery across the skin:
- The concentration of the drug in the vehicle (CV)
- The THERMODYNAMIC ACTIVITY of the drug
what is “thermodynamic activity” of a drug mean? what does it mean if it =1 or is below 1?
Thermodynamic activity is a measure of the escaping tendency of the drug from the formulation (how likely is this drug to leave the formulation).
The thermodynamic activity = 1 when we have a saturated solution. It is very likely for the drug to escape the solution and enter the skin.
If the thermodynamic activity is LESS than 1, this suggests we do not have a sufficient driving force for the drug to leave the vehicle and therefore decrease the rate of mass transport.
What does it mean when a drug is ‘Super Saturated’
If we use a SUPERSATURATED solution, then the thermodynamic activity is above 1 and thus there is a much higher tendency of the drug to escape from the vehicle. e.g ethanol based vehicles.
In topical formulation, define a solution.
Solutions are a single phase, comprised of a solvent (can be aqueous/oil) which may also be formulated with some miscible co-solvents.
what is generally added to solutions for topical administration and explain why?
Miscible co-solvents. They can increase the concentration of the drug. It can be used to modify drug solutbility and get greater concentrations into the solution. E.g with ethanol there is an increase in thermodynamic activity, hence greater flux.
disadvantages of using solution
low viscosity and so poor residence time.
In Topical administration, describe what a lotion is. Do they have any benefits over solutions?
- They are formed of oil-in-water or water-in-oil emulsions
- More common, especially when one phase is volatile resulting in a cooling effect and the formation of a film on top of the skin (e.g. calamine lotion)
- have slightly increased viscosity in comparison to solutions, therefore slight increase in skin residence time.
describe an adhesive patch system
drug inside an adhesive. In these devices there is no rate controlling membrane – we just have the adhesive in contact with the skin. This means that the rate of diffusion/partition of the drug out of the adhesive into the skin is determined by the rate of partition of drug from the skin surface through the deeper layers of the skin
Describe a matrix/layered patch system
Multi layered strategies within this type of patch system aim to slightly reduce the rate of drug diffusion through the patch; this is going to give us slightly different release kinetics compared to a simple adhesive system
What factors of this equation are affected by the presence of penetration enhancers?
Factors affected (increased):
D = Diffusion coefficient (Ease of diffusion through skin) – affected if we make the barrier more permeable)
P = Partition coefficient (partitioning/permeation from vehicle into the skin)
what does a franz cell structure look like?
