Transdermal Biopharmacy Flashcards
what are parenteral drug delivery routes?
any other than the GIT
Parenteral formulations represent ____ of the formulations on the market
2/3
TDS represent ____% of the market share
8
advantages of parenteral drug delivery
control of serum levels rapid efficacy- locally ease of use increased compliance- last longer local delivery fall back if oral routes aren't possible
what is absorbance limited by in parenteral formulation?
by blood flow wherever the drug is injected or cream applied
examples of formulations of IV drug delivery?
solution
suspension
emulsion
reconstituted solids
Iv formulations are usually administered in _____ buffers at ______ pH. examples?
aqueous
neutral
citrate, phosphate, acetate, glutamate
how does drug solubility affect how much is administered?
drug must be completely solubilised so they can act.
If your drug doesn’t solubilise well, you’ll need to inject more to have an effect.
what can be added to improve solubility? examples
Co-solvents may be added to improve solubility or stability e.g. glycerin, ethanol, propylene glycol, polyethylene glycol
TF: particulate matter can be present in IV delivery?
false
don’t want to block vessels
what is an exception where particulate matter can be present?
nutritional lipids- egg yolk phospholipid in oil (<1micron diameter)
____tonic solutions can be used with slow administration
hypertonic
what things can be added for tonicity adjustment?
NaCl, KCl, dextrose
IM drug delivery has a ______ onset of action than IV
slower
IM is ______ rapid than SC. why
more
muscles are more highly vascularised
IM can achieve prolonged release of what? why?
oily and particulate doses
poorly soluble drugs which will sit in the muscle and slowly dissolve
why might wetting agents be included in IM formulations
excipients must retain appropriate viscosity and avoid aggregation
what does drug dissolution dissolve on in IM once in the body?
by the drugs solubility in biological fluids at the injection site
partition coefficient
the higher the blood flow to the tissue the _____ the absorption
higher
deltoid arm muscles- maximum _____ injection volume
2mL
buttock- maximum _____ injection volume
5mL
TF: age and disease eggiest blood flow to the injection site
true
why must we avoid local blood vessels when injecting?
as don’t want to cause haemorrhage in the tissue
SC injection volume range?
where can we inject
0.5-1.5 abdomen arms hips upper back
typically SC drugs are?
in terms of solubility and irritant
water soluble
non-irritant
what type of drugs are good to give SC
poorly soluble
unstable drugs
e.g. insulin
what does IP drug delivery mean
into a cavity or organ e.g. liver, kidney, bladder
examples of IP drug therapy
Chemotherapy for abdominal tumours; peritoneal dialysis in renal failure; diagnostic imaging agents
what is the major route of absorption in IP drug formulations. this means?
portal circulation
1st pass metabolism
what are the risks of IP delivery
bowel puncture
haemorrhage
Transdermal drug delivery has various possible benefits for drugs with poor oral bioavailability. Which one of the following statements is NOT consistent with transdermal drug delivery?
A: Avoids first pass metabolism
B: Avoids food effects
C: Compensates for rapid clearance
D: Achieves sustained drug concentrations in blood
E: Avoids the effects of variable blood flow
E
what part of the skin is through to provide the most barrier to TD absorption
the stratum corneum layer of the epidermis
typical daily dose of drug that can be delivery via TD patch?
meaning?
5-25mg
this drug is limited for using potent drugs as only low doses can be used
typical daily dose of drug that can be delivery via TD patch?
meaning?
5-25mg
this drug is limited for using potent drugs as only low doses can be used
what is maximal skin penetration of the SC achieved by?
- choice of drug and formulation or delivery vehicle to promote absorption
- modification of the stratum corneum – modify enhancers
- choose the potent drug which allow it to penetrate
what are powered penetration enhancement devices? examples?
devices to enhance delivery in TDD
iontophoresis, phonophoresis and electroporation patches
what are the 3 different transdermal penetration routes?
directly across the SC
sweat ducts
via hair follicles and sebaceous glands
which of the 3 TDD routes are most common
through the stratum corneum
for iontophoretic drug delivery (TDD), which of the 3 routes is most common? why?
sweat ducts and the hair follicles/ sebaceous glands
offer the least electrical resistance- based on passing electric current through the skin
what is the SC
bricks (cells) and mortar (lipid rich matrix which sits between the layers of cells
thickness of the SC when dry?
10-15um
thickness of the SC when hydrated?
40um
what are the cells like in the SC
10-15 layers of keratin rich corneocytes which ae DEAD
what is the so called ‘mortar’ of the SC
intercellular lipid matrix extruded by keratinocytes and includes long chain ceramides, free fatty acids, triglycerides, cholesterol, cholesterol sulfate and sterol/wax esters
is the extruded lipid phase of the SC similar to biomembranes?
no
biomembranes contain lots of phospholipids.
how is the extruded lipid phase of the SC arranged?
Hydrocarbon chains arranged into crystalline, lamellar gel and lamellar liquid crystal phase domains within lipid bilayers
what do the first few layers of the extruded lipid phase of the SC rearrange into?
into broad intercellular lipid lamellae – you get layers of lipids sat between the cells
what is water needed for in TDD formulations in regards to the stratum corneum
prevent cracking
maintain suppleness
what component in the skin can effect TDD absorption
Both drugs and excipients may be hydrolysed by enzymes in the skin e.g. esterases, which can affect absorption
what occurs in transcellular TDD? what part of the stratum C is this?
Drugs pass through spaces between the cells – this is where the lipid matrix is.
how is the lipid matrix region arranged?
alternate layers of aqueous regions and lipid regions – lipid lamellae.
what must drugs going through the transcellular route pass?
lipid region
cytoplasm with keratin which impedes movement
what does Fick’s law of diffusion states that steady state flux- uptake of drug through the skin (J) is related to:
the diffusion coefficient (D) of the drug
- the diffusional path length or membrane thickness (h)
- the partition coefficient (P) of the drug between the skin and vehicle of formulation
- the drug concentration (C) applied (assumed to be constant)
what is the ficks law equation
J= DC0P/ h
what is the ideal LogP for TDD drugs
1-3
want it soluble in lipid and aq domains
why do we want the TDD drugs to be soluble in lipid and aq domains?
adequate drug solubility within the lipid domains of the stratum corneum is required to permit diffusion through this region
the drug must also be sufficiently hydrophilic to allow partitioning into the tissues of the epidermis
ideal melting point of the TDD drug
<200 degrees celcius
do we want TDD drug to have polar centres? why?
no
charge would affect solubility in lipophilic regions
ideal half life of TDD drugs?
<6-8 hours
why would a pro drug be used in TDD?
to reduce the amount of charged centres
besides a pro drug how else can the number of charged centres be reduced in TDD drugs ?
Ion pairs, complexes- molecules with charged centres you can make a pair and reduce charge
for optimal permeability we want ____ MW and _____MP
low
low
what must we do when the drug doesn’t have the necessary physiochemical properties to get across the SC
modify the sc
methods of modifying the sc?
Hydration- more water makes the SC swell and separate
Lipid fluidisation- make it easier for the drug to diffuse through the lamellae
Powered electrical devices:
-iontophoresis
-phonophoresis
-electroporation
In a design for an occlusive skin patch for effective systemic delivery of a 600 Dalton, relatively high melting point, weak acid ester drug of LogP ~2 formulated with fatty acids, which of the following effects is least likely to have a significant effect on skin penetration the drug?
A: Swelling of the stratum corneum
B: Formulating a eutectic mixture, lowering the melting point of the drug
C: Disruption of the stratum corneum lipid lamellae
D: Formation of an ion pair increasing the lipid solubility of the drug
E: Hydrolysis by enzymes in the epidermis
D
when is maximum skin penetration rate achieved?
when the drug has the highest thermodynamic activity- when at highest concentration- drug on skin and in the tissues- steep concentration gradient means rapid movement into the tissues e.g. when in a supersaturated solution- highly concentrated reservoir on the skin, produced by evaporation of solvent or by mixing co-solvents
what is the most common mechanism of supersaturation seen clinically?
evaporation of solvent from the warm surface of the skin, resulting in supersaturation; this occurs in many topically applied formulations e.g. creams. Same amount of drug dissolved in less and less vehicle, making it supersaturated
what is an anti solvent?
thermodynamics activity of the drug increases flux by?
when water is absorbed from the skin into the vehicle
5-10 times
supersaturated systems are inherently…..
unstable
prone to crystallisation
what must be incorporated into supersaturated systems to improve stability?
anti-nucleating agents
mixtures of what can provide an anti-nucleating effect and thereby stabilise a supersaturated drug formulation?
Complex mixtures of fatty acids, cholesterol, ceramides in the stratum corneum
what is a eutectic mixture?
two components that at a certain ratio, inhibit crystallisation of each other, thus the melting point of both components is decreased
a eutectic mixture has its MP ______
decreased
example of when you can make a eutetic mixture
Crystal- highly organised, lots of energy needed to break this so thus has a very high melting point. If you inhibit the crystallisation process less energy is needed for the drug to undergo a phase change and the mp decreases
how does MP influence skin penetration
as it influences solubility
the lower the drugs MP, the ______ the solubility in a given organic solvent e.g. skin lipids
GREATER
TF: various eutectic systems for TDD also contain a penetration enhancer as the second component to disrupt and fluidise the lipids. examples?
true
methyl nicotinate with menthol
propranolol with fatty acids
lignocaine with menthol
how is penetration enhancer activity expressed
as enhancement ratio
enhancement ratio equation?
drug permeability coefficient after enhancer treatment/ drug permeability coefficient before enhancer treatment
mechanisms by which penetration enhancers work?
Disruption of the intercellular lipid lamellar structure- fluidising them and making it easier for the drugs to diffuse through
Interactions with intracellular proteins of the stratum corneum to disrupt the structure
Improvement of partitioning of a drug, with a co-enhancer or co-solvent penetrating the stratum corneum
what is widely used to increase skin penetration of hydrophilic and lipophilic agents?
water
effects of water on skin penetration?
increase drug solubility and favours partitioning
Increases skin hydration, swelling and opening of the SC structure, leading to increased penetration
diffusion coefficients of alcohols are _____ following hydration. therefore formulations with alcohol will work better in _______ skin
higher
HYDRATED
The water content of the SC is _____% of the dry weight.
15-20
what does hydration of the sc vary with
external environment
medications
how can medications try to stop the external environment effecting the skins hydration
Occlusion with transdermal patches, plastic films, paraffins, oils or waxes as components of ointments and water-in-oil emulsions that prevent transdermal water loss and keep the skin supple
Oil-in-water emulsions that can donate water into the skin
why does hydrated skin have better permeability
more channels and layers for the drugs to penetrate through
what about lipid nanoparticles aids their penetration through the sc?
the small size
what is fluidisation and fusion of lipids when using liposomes or lipid nanoparticles?
Liposomes hydrate and/or alter lipid layers, especially when lipids are similar to SC lipids: they can readily enter and fuse with SC lipids- Fluidisation and fusion of lipids
what are deformable liposomes or transfersomes?
act as “edge activators”, conferring deformability (flexible) and allowing them to squeeze through channels less than one-tenth the diameter of the transferosome- effective penetration of SC
deformable liposomes or transfersomes can squeeze through channels less than…..
1/10 the diameter of itself
what do deformable liposomes or transfersomes contain?
contain 10-25% surfactant (e.g. sodium cholate) with 3 -10% ethanol
effect of ethosomes?
high alcohol content- fluidises lipids
what are niosomes?
vesicles composed of non-ionic surfactants- aids flexibility
what are solid lipid nanoparticles used for?
carriers for enhanced skin delivery of sunscreens, vitamins A and E, triptolide, glucocorticoids
what do SLNs consist of?
an almost perfect, solid lipid matrix.
where are the drug molecules mostly distributed in SLNs?
around the edge of the SLN
What are NLCs?
Nanostructured lipid carriers (NLCs) are composed of solid lipid matrix immersed in liquid lipid (oil) droplets- mixture of solid lipid crystals immersed in liquid lipid or oil. Part solid part liquid properties
where is the drug distributed in NLCs? why?
uniformly distributed throughout as they have part solid part liquid properties
in lipid nanoparticles, the solid lipid acts as?
matrix to immobilise the drug and prevent nanoparticles from coalescing
in lipid nanoparticles, how does the liquid lipid effects the drug loading dose?
increases the drug loading capacity
why are drug molecules forced to the surface of SLNs
as the solid liquid matrix is almost perfect
SLNs have _____ rapid surface release. why
more
as drugs are concentrated at the surface
why are NLC better for prolonged release?
rapid surface release is prevented
the mixture of lipids of different phases forms an imperfect lipid crystal lattice- can get a higher concentration in. more slow prolonged release
how can keratin in the sc be disrupted?
disrupted using decylmethylsulphoxide, urea or surfactants
what can fluidise lipids?
DMSO, alcohols, fatty acids, terpenes
how to oleic acid and terpenes work?
can extract skin lipids, leaving aqueous channels or microcavities within the lipid lamellae
what happens to the excipients at high drug concentations
excipients pool within the lipid domains to create permeable pores that provide less resistance for polar molecules- excipients would have hydrophilic properties, creates hydrophillic channels to allow the polar molecules to move through the SC
TF: activity relationships have not been described for different permeating agents depending on their chain length, polarity, unsaturation, functional groups
false, they have found relationships
what is a disadvantage of penetration enhancers
enhancers cause skin irritation due to keratin/ lipid disruption. Immune response can be triggered
how do micro needle patches work?
Same as other patches but where the adhesive is there’s microneedles
The stratum corneum is pierced with short needles to deliver drugs into the skin in a minimally invasive manner. Disrupt SC to allow drug to enter
Drugs include small molecules, proteins and nanoparticles, released from extended-release patches
(i) increase skin permeability by creating micron-scale pathways in skin through skin damage
(ii) actively drive drugs into the skin during microneedles insertion
(iii) target the stratum corneum, although microneedles typically pierce across the epidermis and into the superficial dermis too.
examples of micro needle patches?
naltrexone, parathyroid hormone, vaccines
how do drug coated micro needles work?
drug coatedmetal microneedles with drug coated. As patch is applied the needles puncture and force the drug through the SC
how do dissolving micro needles encapsulating drugs work?
- biodegradable polymer, dissolves in skin and releases the drugs. Minimal skin disruption
iontophoresis uses low voltage current to increase what?
permeability of:
o Charged drugs- electric current encourages movement from patch into the skin
o Weakly charged and uncharged drugs, by increasing the electrosmotic flow of water, because of mobile cations in the patch formulation e.g. Na+ and fixed anions (keratin) you get an osmotic imbalance due to the movement of Na into the skin. So you get a flow of water into the skin to correct the osmotic imbalance, the drug moves with this water
how does iontophoresis increase the permeability of charged drugs
electric current encourages movement from patch to the skin
how does iontophoresis increase the permeability of weakly charged and uncharged drugs?
by increasing the electrosmotic flow of water, because of mobile cations in the patch formulation e.g. Na+ and fixed anions (keratin) you get an osmotic imbalance due to the movement of Na into the skin. So you get a flow of water into the skin to correct the osmotic imbalance, the drug moves with this water
the rate of delivery with iontophoresis increases with…..
electrical current
how is the electrical current in iontophoresis controlled?
by a microprocessor or the patient, to enable personalised delivery. Want more drug turn the current up etc.
the maximum current and therefore delivery rate is limited by what in iontophoresis?
skin irritation and pain- if too high and reaches the nerves
what is electroporation used with?
mironeedle patches
how do electroporation powdered patches work?
short high voltage electrical pulses reversibly disrupt cell membranes and skin lipid lamellae in the SC
the electrophores created by electroporation persist for how long? what effect do they have
hours
increase diffusion by orders of magnitude for drugs, peptides, proteins
TF: pores created by electrophoresis are permanent
false, they’re temporary
how is pain and muscle stimulation avoided in electrophoresis?
by using closely spaced microelectrodes, that constrain the electrical field to the SC. Don’t want it to come into contact with deeper nerves
how does phonophoresis work?
Ultrasound: an oscillating pressure wave at a frequency too high for humans to hear- these hit the skin and cause bubble formation. These bubbles oscillate and collapse.
Cavitation energy at the site of bubbles causes small holes to form in the skin; this enhances delivery of lidocaine, insulin, heparin and tetanus toxoid vaccine through the skin
phonophoresis is used to enhance skin permeability to…… how?
small, lipophilic compounds by disrupting the lipid structure of the stratum corneum
______ energy at the site of bubbles causes small holes to form in the skin; this enhances delivery.
cavitation
effect of bubble formation and collapse?
local damage and disruption to the skin
