Parenteral & Transdermal Route of Adminstration Flashcards
Describe the properties of intravenous injections
- Aqueous buffers at neutral pH (citrate, phosphate, acetate)
- Drug must be completely solubilised
- Co-solvents may be added to improve solubility or stability (Ethanol, Glycerin, PEG)
- No particles except for some nutritional lipids
- Hypertonic solutions generally avoid - however possible with slow administration
NaCl, KCl, dextrose often added for tonicity adjustment
What is intramuscular delivery suitable for?
Prolonged release of oily and particulate doses (poorly soluble drugs?
How does blood flow affect absorption of IM injections?
The higher the blood flow, the higher the absorption
- Deltoid arm muscles (2ml max injection volume) provide better absorption than the buttock (5ml max volume) or thigh
- Age and disease affect blood flow
- Degradation may occur at site of injection e.g. proteases affecting protein drugs
What are the advantages of subcutaneous drug delivery?
- Rapid and predictable
- Used for self-medication
- Used for poorly absorbed and fragile drugs
What are the uses of intra-peritoneal drug delivery?
Chemotherapy for abdominal tumours, dialysis in renal failure or for diagnostic imaging agents
Give uses for intra-ventricular drug delivery
Infection OR to reduce side effects in malignancy
How do needle free injections work?
- They force the drug through the skin - they can be spring powered or high pressure gas
- Can be used for SC, Intradermal or IM injection
- Can be reused
- Less pain and damage than using a needle
- Bioequivalent to regular needle-based injections
- Example: IntraJect
How do microneedle patches work?
- The stratum corner is pierced by very fine, short needles
- They increase skin permeability by creating micron-scale pathways in the skin
- Delivers drugs into the skin during microneedles insertion - Minimal invasion
- For small molecules, proteins and nanoparticles
What is the dosage range for transdermal formulations?
5-25mg daily
How can transdermal drug penetration be enhanced?
- Drug and delivery vehicle modification
- Modification of the stratum corneum
- Powered penetration enhancement devices
Give examples of powered penetration enhancement devices
Iontophoresis
Phonphoresis
Electroporation patches
What are the routes of transdermal penetration?
- Directly across the stratum corneum
- Through sweat ducts
- Through hair follicles and sebaceous glands
What are the properties of the stratum corneum?
- 10-15µm thick dry
- 40µm hydrated
- layers of keratin rich corneocytes (dead cells) in an intercellular lipid matrix extruded by keratinocytes
- Extruded lipid phase behaviour is different from biomembranes
- Both drugs and excipients may be hydrolysed by enzymes in the skin e.g. esterases, which can affect absorption
What is the major route for most drugs?
Intercellular route
Route for drugs soluble in lipid regions or in formulation disrupting the lipid regions
What is the route for most hydrophilic drugs?
Transcellular
Hydrophilic drugs penetrate the aqueous regions of keratin filaments - but also have to go through intercellular lipid region.
What is the ideal molecular weight for a transdermal patch?
<500 Da
but can have <1000 Da
What is the ideal melting point for a transdermal patch?
<200°C
What is the ideal LogP for a transdermal patch?
Between 1 and 3
What is the ideal kinetic half life for a transdermal patch?
<6-8 hours
What is the maximum patch size?
50cm2
How can a drug vehicle be modified to enhance skin permeation?
- Drug selection
- Use of pro-drug
- Ion pairs, complexes
- Modification of chemical potential
- Form a eutectic system
- Use liposomes or vesicles
When would you need to modify the stratum corneum?
If the drug doesn’t have ideal physicochemical properties
How can the stratum corneum be modified to enhance skin permeation?
- Hydration (swelling) enhances permeation and gives more routes for drug to pass through
- Lipid fluidisation
- Disruption of the stratum corneum lipid lamellae (provides more routes for drug to pass through)
- Hydrolysis by enzymes in the epidermis (changes nature of drug and therefore its permeation)
What happens when a drug is at its highest thermodynamic activity?
It has maximum skin penetration
This is achieved when drug is in a supersaturated solution
What happens when water is taken up from the skin into the vehicle?
Water acts as an anti-solvent (solvent in which drug is less soluble)
This increases the thermodynamic activity of the drug increases flux by 5-10 times (increases drug permeation)
What is a eutectic mixture?
Two components that, at a certain ratio, inhibit the crystallisation of each other so that the melting point of both is decreased
What is the benefit of having a lower melting point?
The lower the drug’s melting point, the greater the solubility in a given organic solvent
Including skin lipids (reduced to at or below skin temp)
How do penetration enhancers work?
- Disrupt the intercellular lipid lamellar structure
- Form Interactions with intracellular proteins of the stratum corneum
- Improvement of partitioning of a drug, with a co-enhancer or co-solvent penetrating the stratum corneum
How does hydration of stratum corneum improve permeation?
- Alters drug solubility and partitioning
- It increases skin hydration, swelling and opening of the stratum corneum which leads to increased penetration
- Safe and widely used
How do liposomes improve permeation in the stratum corneum?
- They hydrate/alter lipid layers
- Liposome can readily enter and fuse with SC lipids especially when they are similar to the SC lipids
- Deformable liposomes (transferomes) contain ethanol and surfactants.
Act as ‘edge activatiors’ - able to squeeze through channels less than a tenth of their diameter.
How does keratin and lipid disruption improve permeation?
Disrupt the structure of the stratum corneum
Excipients form a homogenous mix with skin lipids, changing drug solubility
Extracts lipids to form aqueous channels or microcavities
At high concentrations they excipients pool within lipids to create permeable pores that provide less resistance for polar molecules
What is the effect of shifting the solubility parameter on permeation?
Shifting the solubility parameter of the skin closer to the drug increases solubility and so increases drug permeation.
What are the advantages of parenteral drug delivery?
- Improved control of: onset of action, serum levels, tissue concentration, elimination
- Rapid action
- Enhanced efficacy
- Can be administered to unconscious or uncooperative patients
- Increased compliance e.g. via depot injections or patches for contraceptives, mental health
- Local/targeted drug delivery
- Fall back route when oral route is not possible
What affects the absorption of parenteral drugs?
Poor/variable blood flow
What is referred to as percutaneous administration?
Intramuscular, intravenous, subcutaneous, intradermal (dermis layer)
What is referred to as percutaneous administration?
Intramuscular, intravenous, subcutaneous, intradermal (dermis layer)
Volume of injection is limited for IM, SC and ID routes
Describe the characteristics of IM injections
- Less rapid action than IV but more rapid than SC
- Prolonged release of poorly soluble drugs
- Excipients must maintain an appropriate viscosity and avoid aggregation (wetting agents)
- Dissolution of drug affected by solubility in biological fluids at the injection site
- Partition coefficient of the drug is also important
Describe the characteristics of SC injections
- Used for solutions or suspensions
- Rapid and predictable profile
- Can be used for self medication due to low infection risk
- Generally used for poorly absorbed, unstable drugs (insulin)
- 0.5 - 1.5ml injection volume
Describe the characteristics of Intra-peritoneal (IP) injections
- Injection into a cavity or organ
- Major route of absorption is the portal circulation, leading to 1st pass metabolism
- Smaller, lipid soluble drugs are absorbed faster than larger water-soluble drugs
- Have to be careful to avoid bowel puncture
What are the benefits of transdermal drug delivery?
- Avoids first pass metabolism
- Avoids food effects
- Compensates for rapid clearance via rapid delivery (permeable skin)
- Avoids sustained drug concentrations in blood
What are the limitations of creams, gels and patches?
Difficulty passing stratum corneum
Only potent drugs can be used (5-25mg)
How is the stratum corneum kept supple?
Water is essential as a plasticiser to prevent cracking of the SC and to maintain suppleness
Fick’s law of diffusion states that steady state flux (J) is related to what?
- The diffusion coefficient (D) of the drug
- The membrane thickness (h)
- The partition coefficient (P) of the drug between the skin and vehicle
- The drug concentration (C) applied (assumed to be constant)
J = DCP/h
What properties are ideal for diffusion through skin?
- Both solubility and partition coefficient affect drug diffusion
- An “intermediate” log P in octanol/water of 1 – 3 is ideal
- The drug must be:
Lipophilic enough to travel through lipid domains of the stratum corneum
Sufficiently hydrophilic to allow partitioning into the tissues of the epidermis
What solubility is ideal for diffusion through skin?
An “intermediate” log P in octanol/water of 1 – 3 is ideal
The drug must be:
- Lipophilic enough to travel through lipid domains of the stratum corneum
- Sufficiently hydrophilic to allow partitioning into the tissues of the epidermis
> 3 will partition through lipid but not aqueous
<1 will partition through aqueous but not lipid
What properties are ideal for drugs administered through the transdermal route?
LogP 1-3 MW <500 Da MP <200°C No or few polar centres (carboxylate or zwitterions) Short half life <6-8hrs Max. patch size of SA = 50cm^2 5-20mg max dosage p/day
How do lipophilic and hydrophilic molecules differ in onset of action?
More lipophilic drugs will take longer to partition through lipid layer of the skin and therefore exhibits a slower depot-like effect in rise in plasma
How can you hydrate the stratum corneum?
Expansion causes large cavities, allowing drug to pass through
Done using oil in water emulsions, moisturiser, patches
How do liposome/lipid particles alter the stratum corneum?
Alters properties of lipid layers
Deformable liposomes can alter their shape, enabling them to fit through small channels
How are supersaturated and saturated solutions formed?
Topically applied formulations
Evaporation of solvent due to the warm surface of the skin results in supersaturation
What are the limitations of supersaturated solutions? How can they be improved?
Supersaturated systems are inherently unstable and require the incorporation of anti-nucleating agents to improve stability.
Anti-nucleating agent = complex mixtures of fatty acids, cholesterol, ceramides in the stratum corneum
What are common second components of eutectic systems?
Penetration enhancers e.g. Ibuprofen with terpenes Methyl nicotinate with menthol Propranolol with fatty acids Lignocaine with menthol
How is penetration enhancer activity expressed?
Expressed as enhancement ratio (ER).
ER = permeability coefficient after enhancer/permeability coefficient before enhancer
What external factors affect the hydration of skin?
- Occlusion with transdermal patches, ointments and water-in-oil emulsions that prevent water loss
- Oil-in-water emulsions that can donate water into the skin
How much water content does the dry weight stratum corneum contain?
15-20%
How does hydration of the SC affect the diffusion coefficient of alcohols?
Diffusion coefficient is 10x higher
What are solid lipid nanoparticles?
Carriers for enhanced skin delivery of drugs in sunscreens, vitamin A and E, glucocorticoids
How do solid lipid nanoparticles work?
Consist of an almost perfect, solid lipid matrix which forces encapsulated drugs to the surface of the particle.
How do solid lipid nanoparticles work?
Consist of an almost perfect, solid lipid matrix which forces encapsulated drugs to the surface of the particle.
Thus more drugs can be encapsulated and rapid surface release is prevented.
How do nanostructure lipid carriers worK?
Composed of solid lipid matrix immersed in liquid lipid (oil) droplets.
The solid lipid acts as a matrix to immobilize the drug and prevent nanoparticles from coalescing, whereas the liquid lipid component increases the drug loading capacity.
The mixture of lipids of different phases forms an imperfect lipid crystal lattice. Results in rapid drug release.
How can keratin in the skin be disrupted?
Using decylmethylsulphoxide, urea or surfactants
How can lipids in the skin be fluidised?
Using DMSO, alcohols, fatty acids, terpenes
How can optimal penetration enhancement be achieved?
Structure – activity relationships
Optimal penetration enhancement with:
- C18 unsaturated alkyl chains
- Saturated alkyl chain lengths of C10-12 attached to a polar head group
What is the disadvantage of penetration enhancers?
Cause skin irritation
Pores in skin allow microbes to enter
Give examples of permeation-enhancing excipients
- Alcohols (Propylene glycol) Fluidise lipid bilayer - Triglycerides, Stearates Form homogenous mix with skin lipids, disrupting lipid bilayer Longer chains more effective - Water Hydration - Solvent (Dimethyl isosorbide) Dissolves lipids - Oil - Surfactants (PEG/Macrogol) Potent penetration enhancer
What is the difference between permeation and skin absorption?
Permeation = Through the skin and into the blood
Skin absorption = No permeation, drug has gone through the skin and into the lipid layer and is retained there
Describe the action of ester drugs through the skin
- Ester drugs are uncharged
- Will not form ion pairs
- Hydrolysis of esters by skin esterases will lead to charged byproducts which will be more hydrophilic and have improved permeation in aqueous regions
What are the advantages of microneedles?
- Increase skin permeability
- Actively drive drugs into the skin
- Target the stratum corneum
(can reach epidermis and superficial dermis too)
Give examples of microneedles
Vaccines, Naltrexone, Parathyroid hormone
What are the unconventional types of microneedle patches?
Drug coated needles Dissolving microneedles containing the drug Solid microneedles Rapidly separating microneedles Hollow microneedles
What is iontophoresis (powered patch)?
Low voltage current is used to drive the drug into the skin Electro-osmotic flow of water can help to move charged drug Via mobile cations (Na+) and fixed anions (Kerations) which repel the drug into the skin The rate of drug delivery increases with electrical current Maximum current (drug delivery) limited by skin irritation and pain
What is the benefit of iontophoresis?
Provides control over drug dosing, because delivery is proportional to the amount of charge (product of current and time)
What is electroporation (powered patch)?
Short, high-voltage pulses reversibly disrupt lipid layers
Reduces resistance of SC via creation of electro-pores
Increase diffusion by orders of magnitude
Effect lasts for hours
Why and how is the voltage effects of electroporation limitated to the SC?
If the electrical field was allowed to reach deeper, this would affect sensory and motor neurons
Leads to pain and muscle stimulation
Avoided by using closely spaced microelectrodesthat constrain the electrical field to the SC.
What is phonophoresis (powered patch)?
- Low frequency ultrasound is used to make small lipophilic structures more permeable
- Disrupts lipid structure of SC via formation of bubbles which collapse due to oscillations from ultrasound
- Cavitation energy at the site of bubbles causes small holes to form in the skin
Pulsed lasers can also increase skin permeability using a related shockwave mechanism
Give examples of drugs for which phonophoresis is used to enhance transdermal delivery
Lidocaine
Insulin
Heparin
Tetanus toxoid vaccine
