Drug Delivery to the Skin - 3

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  • Created by: LBCW0502
  • Created on: 08-02-20 11:09
Which factors affect drug absorption?
Membranes, skin, route, compounds, skin types, modelling
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Describe features of drug absorption - membranes
No active transporters/mechanisms in the skin (keratinised layer).
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Describe features of drug absorption - skin (1)
Drugs need to by-pass stratum corneum via simple/passive diffusion to get into the skin.
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Describe features of drug absorption - skin (2)
Corneocytes (proteins, bricks) – cornified cells (cells release water content, dried out, membrane popped, proteins dried out)
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Describe features of drug absorption - skin (3)
Lipids (mortar) – from cells being popped, also comes from the outside, constantly secreted lipids from cells. Corneocytes and lipids affects route of penetration
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Describe features of acne
Acne – hormonally driven, over secretion of liquid (oil/lipid rich) covers cells (sometimes penetrates the skin)
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What are the two main sources of lipids?
From cells and from sebum
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What would happen if a lipophilic drug was applied to the skin? (1)
Lipophilic drug – goes via paracellular route (large difference for drug delivery to the skin compared to other formulations). Other drugs/routes – usually travel via transcellular route. All stratum corneum is lipophilic
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What would happen if a lipophilic drug was applied to the skin? (2)
Paracellular route takes longer compared to transcellular route (e.g. corticosteroids take 2-3 days to be effective)
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What would happen if a hydrophilic drug was applied to the skin? (2)
Hydrophilic drug e.g. caffeine – via proteins, via transcellular route (usually faster route)
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What are the barriers to drug delivery to the skin? (1)
Stratum corneum goes under hair follicle (stratum corneum is weaker at the bottom inside the hair follicle). Hair follicle – holes, containing sebum, not much drug can pass through (some drugs may pass through hair follicle)
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What are the barriers to drug delivery to the skin? (2)
Sweat glands – usually generate water, drugs may not pass through
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Is the epidermis hydrophilic or lipophilic?
Hydrophilic
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What is the issue with the route of drug delivery to the skin? (1)
No technique sensitive to distinguish between paracellular and transcellular routes in the skin
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What is the issue with the route of drug delivery to the skin? (2)
Most drugs will take all the routes, get into the skin whichever way possible, some routes more preferred than others (but can’t be measured)
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Describe features of drug absorption - route (1)
Transappendageal (shunt route) - 0.1% of skin surface. Intercellular - principle pathway for small/uncharged molecules, possible for hydrophilic molecules, highly tortuous, permeates passing through continuous lipid domains
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Describe features of drug absorption - route (2)
Transcellular - hydrophilic/charged permeants, still involves crossing of lipid domains, pathway directly across S. corneum, shorter pathlength
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Describe features of drug absorption - compounds (1)
Types of molecules getting into the skin. Small/permeable (absorbed by skin cells), large/non-permeable (temporarily absorbed by glands), large/non-permeable (goes between skin cells)
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Describe features of drug absorption - compounds (2)
Compounds have similar physico-chemical properties e.g. mass, pKa, log Ka. E.g. nicotine (mass 162.2, pKa 2.2, 8.86, log K 1.27) patches, betamethasone valerate cream (mass 476, pKa N/A, log K 3.73). Log P and mwt – most significant factors
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Describe features of drug absorption - compounds (3)
Potts and Guy equation used to predict drug absorption across the skin (permeability coefficient) prior to testing/formulation/determine safety. log Kp = -6.3 + 0.71 log K o/w - 0.0061 MW
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Describe features of drug absorption - compounds (4)
Plot for predicted log Kp against observed log Kp
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What are the ideal properties for compounds used in drug delivery to the skin? (1)
Low mwt (<400). Log P (octanol/water partition coefficient) of 1-3. Low m.p point (ability of compound to interact with components e.g. high m.p. will need to interact with lipids to get into skin, lidocaine/little interactions, gets into skin)
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What are the ideal properties for compounds used in drug delivery to the skin? (2)
Skin solubility, partition coefficient, size and ionisation state of drug are all important
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Why is it difficult to delivery antibiotics to the skin?
Most antibiotics have a negative log P – unable to deliver to the skin e.g. as a patch
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State features of the Potts and Guy equation
Potts and Guy equation – demonstrates natural absorption of a gel/cream into the skin. Attempt to prove concept wrong – modify skin structure to enable a range of drugs to get into the skin
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What are the important aspects of patient counselling for medicines being delivered to the skin? (1)
Patient counselling – position of drug on the skin (skin is not homogenous in terms of temperature and thickness of the layer). Eye-lid – thinnest stratum corneum layer (PE – keep corticosteroids away from eyes)
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What are the important aspects of patient counselling for medicines being delivered to the skin? (2)
Stratum corneum – thickest layer on hands and feet (difficult to treat infections on hands and feet due to thick layer)
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Describe features of drug absorption - skin types (1)
Skin types (ethnicity) – light coloured skin (thin layer of stratum corneum), dark coloured skin (more hydrated skin, thicker stratum corneum)
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Describe features of drug absorption - skin types (2)
Age - hydration/blood flow decreases with age, neonatal skin is more permeable lose collagen (smaller collagen layer), lose thickness of dermis, stratum corneum gets dehydrated (skin becomes itchy)
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Describe features of drug absorption - skin types (3)
Retinoic acid – reduces rate at which collagen is lost (issues with cosmetics claiming to replace collagen - not possible, very large structure, difficult to get into the skin)
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Describe features of drug absorption - skin types (4)
Get older – skin releases cytokines into the body (inflammation – health problems e.g. cancer). Anatomical site (genital > head/neck > trunk > arm > leg). Race (significant difference in S.corneum for water content)
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Describe features of drug absorption - skin types (5)
Metabolism (enzymes slow down, skin contains many drug-metabolising enzymes, phase I and II). Desquamation and drug binding. Skin condition and disease (skin cancer more prevalent)
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Describe features of Fick's first law of diffusion (1)
J = -D dc/dx (where J=flux of permeant, D=diffusion coefficient, dc/dx=conc. gradient). Larger particles (slower diffusion rate), smaller particles (faster diffusion rate)
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Describe features of Fick's first law of diffusion (2)
Gradient – from high concentration to low concentration (drives diffusion of drug into the skin). Understand rate of transport e.g. applied to patches. Whilst drug is on the skin, diffusion is constant
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What would happen if a patient removes a patch/the patch falls off? (1)
If patient removes patch form the skin/patch falls off the skin, apply new patch (adhesive removed from old patch), new patch delivers drug at the same rate (*concentration gradient, rate). Concentration is an approximation – don’t know concentration
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What would happen if a patient removes a patch/the patch falls off? (2)
Patch places on hair – hair will remove patch eventually, hair lifts (insulation, barrier)
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What is Fick's second law (with simplification)?
dm/dt = D Co/h. (where M=cumulative mass of permeant that passes through per unit area in time t, Co=permeant conc. in first layer of skin, h=skin thickness)
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The rate of drug transport into the skin depends on which factors?
Drug diffusion coefficient (drug properties), partition coefficient (type of vehicle), diffusion gradient, thickness of barrier
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Does a lipophilic drug in lipid vehicle give a higher or lower partition coefficient?
Lipophilic drug in lipid vehicle – lower partition coefficient (favours lipid rich areas)
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Does a lipophilic drug in hydrophilic vehicle give a higher or lower partition coefficient?
Higher partition coefficient - drug will move away from aqueous environment into lipid rich area in the skin. Gel – works quicker in active form
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What are the equations to model drug absorption?
Partition coefficient - P = Co/Cv (Cv=permeant conc. in vehicle). [dm/dt = DP Cv/h].
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Describe features of drug absorption - modelling (1)
Plot – cumulative amount per unit area against time – lag time (e.g. lidocaine for pain), gradient (determine diffusion coefficient, flux)
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Describe features of drug absorption - modelling (2)
Kp = PD/h. J = Kp Cv
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Describe features of drug absorption - modelling (3)
Permeability coefficient – every drug ranked based on permeability, obtain Kp (understand natural penetration of drug into the skin), Kp (cm/h) used in comparisons
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Describe features of drug absorption - modelling (4)
Most of the drug applied to the skin doesn’t absorb (e.g. 2% of betamethasone cream is absorbed)
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Describe features of drug absorption - ignoring vehicle effects on skin (1)
Driving force of gradient (high) – main driving force. Rate depends on thermodynamic activity, diffusion coefficient, activity coefficient in skin and thickness of skin layer. dm/dt = αD/γh
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Describe features of drug absorption - ignoring vehicle effects on skin (2)
Driving force of passive transport is chemical potential gradient across the skin. Different vehicles have different capacities to dissolve drug
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Describe features of drug absorption - ignoring vehicle effects on skin (3)
Thus, at a fixed drug concentration different vehicles will have different drug activities. To maximise delivery, formulate as close as possible to maximum solubility (i.e. TA=1)
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Describe features of drug absorption - ignoring vehicle effects on skin (4)
Alpha = Cv/Css (conc in vehicle/sat conc). Css = 1 mg/mL. Cv = 1 mg/mL. Thermodynamic activity = 1
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Describe features of drug absorption - ignoring vehicle effects on skin (5)
Maximum thermodynamic activity (is the saturated concentration). Plot – C (passive penetration) vs time. Thermodynamic activity is proportional to the flux
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Describe features of drug absorption - ignoring vehicle effects on skin (6)
Beclomethasone in water Css = 1mg/mL. Beclomethasone in water Css = 0.5mg/mL (vehicle changed, solubility will be different), max solubility is now 0.5 mg/mL
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Describe features of drug absorption - ignoring vehicle effects on skin (7)
Corticosteroids – formulations modified to use small amount of drug, different vehicle used, produces same/effective clinical outcome
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Describe features of drug absorption - thermodynamic activity
Thermodynamic activity = Degree of drug saturation (DS). DS = Cv/SCv (where Cv = the drug concentration in the vehicle SCv =saturated concentration in the vehicle). Up to a degree of saturation of 1 = thermodynamically stable. DS >1 = supersaturated
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