Modified release lecture 2/2 - transdermal drug delivery Flashcards
Describe how to microencapsulate a drug
Simply coating (e.g. by spray) the surface of drug particles with polymer to slow down water penetration and hence dissolution
What MR designs can be microencapsulated?
e.g. -resinates of strong cationic drugs can be formulated as sustained release suspension, tablets capsules or microparticles
how do ion exchange resins work?
Ionised drug binds to a polymeric (insoluble) resin (usually 1-2mm bead) through opposite chargers -drug-resin then milled to get a smaller particle size -particles then packed into a capsule, tableted or suspended in liquid -can be modified further for use in monolithic, reservoir and microencapsulated type systems
Release mechanism of ion exchange resins?
Simple ion exchange in the GIT where electrolyte concentration being high can change the drug for another counter ion
Example of ion exchange resin
nicorette is a nictionine complex with a cation exchanger
Give an advantage of using ion exchange resins
Reduced risk of dose-dumping
ion exchange resins… 1) basic drugs (salt form or free base) bind to what exchange resin type? 2)what about acidic drugs?
1) cationic exchange resin (resin itself is an anion) 2) anion exchange resin (resin itself is a cation)
Describe the Continus [10] tablet system from a formulation point of view
-API in a mixture of hydrated and hydroxyalkyl cellulose and higher laiphathic alcohol
Mechanism of release for a Continue [10] tablet system?
Dissolution of the higher aliphatic alcohol and dissolution of the drug through the hydrated hydroxyalkyl cellose
For Continus [10] tablet systems, what decides the rate of release?
Relative amounts of hydroxyalkyl celluloses and higher aliphatic alcohols plus extent of hydration
Describe the MST Continus Suspension granules formulation
-Morphine bound to ion exchange resin beads -Mesh cationic exchange resin -pink granules
What is the release mechanism for MST Continus Suspension granules?
-Morphine displaced by sodium and potassium ions present throughout the GIT -plasma profile is comparabe to that of the MST CONTINUS tablet -the morphine-free resin is then excreted
Describe the Zomorph formulation
-Zomorph modified release capsules -pellets contained in a capsule shell determines the dose of morphine sulphate -morphine sulfate+binding agent –> spheres - -then coat with ethyl cellulose as a suspension and dry. This coat envelopes each pellet, thickness of the coat determines the release characteristics
Release mechanism for Zomorph MR Capsules?
Diffusion of the active material across the ethylcellulose coat
Why should you NOT crush or chew Zomorph capsules/pellets?
-crushing or chewing of the pellets will destroy the ethylcellulose coat, therefore will alter the product’s release profile
Describe the formulation of MXL capsules
-powdered morphine + hydrophobic wax (hydrogenated vegetable oil) and cooled to give multi-particulates of diametre 0.25-1.8mm -with evenly distributed drug in wax. These are then encapsulated
Release mechanism of MXL capsules?
-capsules disintegration (~15mins) -water enters the multiparticulates and morphine diffuses out of each particle
Why must morphine sulfate extended-release tablets be taken whole? Why is chewing, crushing or dissolving the tablets not allowed?
Crushing, chewing or dissolving the morphine extended-release tablets/capsules will result in uncontrolled delivery of morphine and can lead to overdose or death
Advantages of transdermal drug delivery?
-simple and safer administration and termination of therapy -avoids first pass metabolism -near constant therapeutic concentrations over extended time -patient compliance -reduces need for multiple dosing
What are the disadvantages of transdermal drug delivery?
-higher product cost -limited drugs which can penetrate skin barriers -need to be potent drugs as the patch size is small
Imagine a pin goes right through your skin, what layers of skin will it go through, from outside to inside?
Epidermis Dermis Subcutaneous fat
4 layers of epidermis from outside to inside?
Stratum corneum Stratum granulosum Stratum spinosum Stratum basale
Stuff in dermis?
-sweat ducts -sebaceous glands -arrector pilli muscles -hair follicles
stuff in subcutanous tissue?
-blood vessels -fat lobules
Functions of skin
-barrier -support -thermal -cushion -insulation
surface pH of skin
pH~5
Routes for drug to enter skin
-Intercellular route -intracellular route -shunt routes
Features of dermis
-comprises collagen, elastin and polysaccharides -water rich -has blood supply -helps maintain temperature -can remove permeating solutes -has nerve supply -sink conditions for drug absorption
Where in the skin is the… 1) Cutaneous microcirculation 2) systemic circulation
1) dermis 2) subdermal issue
Substances that permeate the stratum corneum well
-moderately polar, amphiphillic (logP range 1-5) -unionised -tend to form hydrogen bonds -low molecular weight (<500)
examples of drugs that can permeate the stratum corneum
Estradiol Fentanyl Nicotine
Factors that increase permeation of the stratum corneum
-hydration of skin -higher temperature -broken or peeled skin
2 General types of TDS
-reservoir -matrix
Describe the reservoir TDS system
-Tighter control but higher risk of dose dumping -release controlled by diffusion through a membrane -in simplest form, space between impervious backing layer and rate-controlling membrane (RCM) provides a reservoir for the drug to be contained -RCM is coated with thin layer of adhesive polymer matrix
Describe the matrix TDS
release controlled by diffusion through a polymer matrix
Discuss the basic components of a patch
-drug(s) in polymer matrix or reservoir -penetration enhancers (accelerants) interact with stratum corneum to alter structure -adhesive, pressure sensitive and compatible with drug and all excipients -protective release liner, chemically inert, disposable and usually occlusive to prevent loss of volatiles -outer backing laminate, flexible but good tensile strength
example of a TDS penetration enhancer/accelerant
Sodium lauryl sulfate
Examples of TDS adhesives
-polyacrylate -polyisobutylene -polysiloxane
Examples of outer backing laminates for TDS
-paper, plastic or foil -polyesters -elastomers -ethylene vinyl acetate (EVA) -aluminised plastic laminate
What is the TDS design criteria?
1) Delivery rate should be constant (and less than permeability of least permeable skin) 2) Adhesive and vehicle have to be non-irritating 3) Vehicle should have necessary physicochemical properties permitting prompt release of drug 4) System should occlude the skin to ensure one-way flux of drug
J=(Km D Cv)/L what do these letters stand for?
J= permeation rate (flux) D=drug diffusion coefficient Km=vehicle-membrane partition coefficient Cv=drug concentration in the vehicle Cm= Conc of drug in skin Km=Cm/Cv
4 ways to maximise transdermal drug delivery?
-have drug at its saturation solubility in the vehicle -use a vehicle which modifies the skin barrier (e.g. occlusives, accelerants) -use a vehicle having a low affinity for the drug (enabling the drug to partition into the SC) -Choose a skin site with low thickness
Give 3 TDS commercial examples
-Butran - Buprenorphine -Nitro-Dur & Transderm Nitro deliver Nitroglycerin -Fentanyl, many brands, mostly matrix-based
Describe an adhesive diffusion-controlled transdermal patch
Drug directly dispersed in adhesive layer
Adhesive characteristics for TDS?
- Should allow migration of active drug
- Should enable the device to adhere to contours and flexible points of the skin (dependent on the size, thickness and flexibility of the device).
- Generally contains active drug to act as a quick acting priming dose.
- Should enable device to remain on the skin for a specified period of time (from one to several days)
Butrans patch
The layers are
(1) a beige-colored web backing layer; (2) an adhesive rim without buprenorphine; (3) a separating layer over the buprenorphine-containing adhesive matrix; (4) the buprenorphine containing adhesive matrix; and (5) a peel-off release liner. Before use, the release liner covering the adhesive layer is removed and discarded.
matrix-disperson-type TDS patch
example?
example:
. Nitro-Dur Patch ; Nitroglycerin as solid dispersion in hydrophilic Polymer matrix
Drug release ∝ patch area ; 500 µg /cm2 /day
membrane-moderated TDS patch
E.g. Transderm-Nitro Patch ; Treatment of angina
Nitroglycerin as solid dispersion in hydrophilic liquid silicone matrix
Membrane: Porous ethylene vinyl acetate copolymer releases 500 µg nitroglycerine /cm2 /day
fentanyl patches
- Fentanyl is soluble in both fat and water; with a low molecular weight and high potency, it is ideal for transdermal delivery.
- Both reservoir and matrix type designs are available for Fentanyl.
- Matrix patches are most common
A reservoir patch is no longer available in the UK as open to drug abuse by cutting the patch open
other delivery systems not discussed in this lecture series
- Chemically linked to biodegradable polymers
- Stimuli responsive DDS
- Nanoparticle drug delivery systems
