Modified release Flashcards
Advantages for modified release?
Peaks & troughs minimised – steady state therapeutic levels to better manage disease
Improved Compliance- less xxxazsxsdweffrequency doses
Better safety margin- Lower side effects
Efficient use of drug – lower overall amount used
Reduction in healthcare costs- less monitoring, shorter treatment time, less dispensing.
Disadvantages for modified release?
Risk of dose dumping & instability of drug, more costly manufacturing process.
Delayed Release:
The drug is not released immediately following administration but at a later time
e.g. enteric-coated tablets or capsules.
Repeat Action:
An individual dose is released soon after administration. Second or third doses are released at later intervals
Prolonged Release:
The drug is absorbed over a longer period of time than from a conventional dosage form. Implication that onset is delayed because of slower release rate from the dosage form.
Sustained Action:
An initial release of drug sufficient to provide a therapeutic dose soon after administration. Then a gradual release over an extended period.
Extended Release (ER):
Release drug slowly.
Plasma concentrations are maintained for a prolonged period of time (usually between 8 and 12 hours)
Controlled Release (CR):
Controlled Release (CR):
In literature you will find the terms PR and SR are interchangeably used with ER. They terms must not be confused with delayed releaseRepeat-action Versus Sustained-action Drug Therapy?
A repeat-action tablet can be distinguished from sustained-released.
Repeat-action does not release the drug in a slow controlled manner.
Repeat-action tablet usually contains two doses of a drug:
The first is released immediately after administration.
The second dose is delayed. Often by an enteric coat.
Layered tablet – comprises 2 or 3 layers
Tablet within a tablet
MR products are generally designed to provide either:
Prompt achievement of a plasma concentration of drug :
- remaining constant within the therapeutic range of the drug for a prolonged period of time. OR
- declining at such a slow rate that the plasma concentration remains within the therapeutic range for a prolonged period of time.
Suitable drugs for MR?
- Biological t1/2 = 2-8hrs
- High therapeutic window
- Log P = ~2.2-3.3
- uniformly absorbed and not too unstable throughout the - - GIT
- Moderate potency – require small doses
Several physiochemical properties of the active drug can influence the choice of dosage form. The properties include
aqueous solubility and stability; pKa; partition coefficient (or, more appropriately, permeability values) and salt form.
The aqueous solubility and intestinal permeability of drug compounds are of paramount importance.
In practice difficult to achieve ideal drug release rates in mass balance with clearance to achieve constant plasma levels. This is due to many factors, e.g. ;
- Variable physiological conditions of GIT
- Clearance rate can be patient dependent, age, race etc
- Disease status
- Food/diet intake
The Physiology of the Gastrointestinal Tract and Drug Absorption.
It has been reported that:
Solution and pellets (<2mm) leave the stomach rapidly;
Single dose units (>7mm) can stay in the stomach for up to 10 hours if the delivery system is taken with a heavy meal;
The transit time through the small intestine is approximately 3 hours
Choice of Dosage Form:
Single-unit dosage forms include tablets, coated tablets, matrix tablets and some capsules.
A multiple-unit dosage form includes granules, beads, capsules and microcapsules.
Modified-release dosage forms include inert insoluble matrices, hydrophilic matrices, ion-exchange resins, osmotically controlled formulation and reservoir systems.
Ornade Spansule?
Each capsule is so prepared that an initial dose is released promptly and the remaining medication is released gradually over a prolonged period.
Main Classes of Modified-Release Dosage Forms
For convenience of description modified release oral delivery systems can be considered under the following main headings:
Monolithic or matrix systems
Reservoir or membrane-controlled systems
Osmotic pump systems
The two basic mechanisms controlling drug release are:
Dissolution of the active drug component
Diffusion of dissolved or solubilized species
Within the context of the mechanisms controlling drug release there are four processes operating:
Hydrating of the system (swelling of the hydrocolloid or dissolution of the channelling agent)
Diffusion of water into the system
Dissolution of the drug
Diffusion of the dissolved (or solubilized) drug out of the system.
Many formulation techniques are used to ‘build’ the barrier into the peroral dosage form.
for example–>
The use of coatings
Embedding of the drug in a wax or plastic matrix
Microencapsulation
Chemical binding to ion-exchange resin
Incorporation in an osmotic pump
Matrix system?
Drug uniformly distributed in matrix
Can not usually get zero order release
Rate declines with time
How does a wax matrix delivery system work?
Drug contained in hydrophobic matrix which remains intact during release of the drug
In contact with the aqueous media the channeling agent dissolves and leaches out of the compact leaving a porous matrix of tortuous capillaries.
The drug dissolves and diffuses out of the system via the capillaries
The rate of release is governed by both the dissolution and diffusion of the channeling agent and the drug.
Matrix forming agents for wax matrices?
- almost any hydrophobic material that is solid at room temp and doesn’t melt at body temp
Channeling agents for wax delivery system?
Almost any water soluble pharmaceutically acceptable solid material.
How do hydrophilic matrix delivery systems function?
1) hydrophilic colloids swell in contact with water to form a hydrated matrix
2) The system compromises a mixture of drug, hydrophilic colloid, any release modifiers and lubricant/glidant
2) hydrated matrix layer controls the further diffusion of water into the Matrix and diffusion of the drug through the hydrated matrix layer controls the rate of release of the drug
3) the outer hydrated matrix layer will erode as it becomes more dilute
Reservoir System:
Active drug In core
Coating
Reservoir system release controlling membrane polymer:
Requirement is that the polymer remain intact for the period of release examples = ethyl cellulose
Osmotically-controlled Systems:
These are single unit dosage systems in which osmotic pressure is used as the driving force to generate a constant rate of drug release.
The simplest system is the “elementary osmotic pump” (OROS®). The pump is presented as a tablet dosage form and consists of a core of drug, usually combined with an osmotically active agent, coated with a rigid, non-swelling semi-permeable membrane such as cellulose acetate.
The membrane permits the passage of GI fluid but not drug or electrolyte.
Osmotic pump delivery system mode of action:
- drug is included in a tablet core which is soluble and which will solubilise the drug in the presence of water
- the core is coated with a semi permeable membrane which allows water to pass through into the core which dissolves
- as the core dissolves a hydrostatic pressure builds up which forces drug solution through a hole in the coating
- rate of release is governed by the rate at which the water is able to pass through the membrane and how fast drug solution can pass out
Advantages of an osmotic pump:
- well characterised and understood
- release mechanism not drug dependent
- coating technology straightforward
- suitable for wide range of drugs
- zero order release profile
Microencapsulation
Simply coating (e.g.. by spray) the surface of drug particles with polymer to slow down water penetration and hence dissolution.
Common materials used in modified release products for oral delivery
Mixture of Waxes (beeswax, carnauba) with fatty acids and cetyl alcohol. Gives coatings which are slow to break down in the GI tract.
Shellac and Zein : remain intact till pH in the gut is less acidic.
Ethylcellulose- used to provide membrane. Quite stable in the GI tract and lets water (or drug dissolved in water) to permeate.
Cellulose acetate – forms semipermeable membrane
Ion exchange resins
Ionised drug binds to a polymeric (insoluble) resin (usually 1-2mm bead) through opposite charges. This can be done by incubation or passing through ion exchange column.
Drug-resin is then milled to obtain smaller particle size
The particles are packed into capsule, tableted or suspended in liquid. Such particles could also be modified further to be used in monolithic , reservoir and microencapsulated type systems.
Release mechanism is simple ion exchange in the GI tract where electrolyte concentration being high can exchanges the drug for another counter ion.
Example Nicorette is nictionine complex with cation exchanger.
Advantage- Drug-resinates reduces risk of dose dumping.
Basic drugs in ion exchange resin?
Bind basic drugs (salt form or free base) bind to cation exchange resin
e.g. Resin-SO3- .
See below.
Resin-Drug+ (+) X+ –> resin-X+ (+) drug
MST Continus®Suspension granules release:
Release mechanism : Morphine displaced by sodium and potassium ions present throughout the gastrointestinal tract. Plasma profile is comparable to that of the MST CONTINUS tablet.
The morphine-free resin is then excreted.
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 decides release characteristics.
Release mechanism: Diffusion of the active material across the ethylcellulose coat.
Crushing or chewing of the pellets will destroy this coat and therefore alter the products release profile.
Typical skin surface pH
5
Dermis composition:
Comprises collagen, elastin polysaccharides. It is water rich and
- Has blood supply
- Helps maintain temperature
- Can remove permeating solutes
- Has nerve supply
Permeation of Stratum Corneum:
Substances that penetrate well:
- Moderately polar, amphiphilic
(log P in the range 1-5)
- Unionized
- Tend to form Hydrogen bonds
- Low molecular weight (typically <500)Factors that can increase permeation
- Hydration of skin
- Higher temperature
- Broken or peeled skin
General types of TDS
Reservoir – Tighter control but higher risk of dose dumping.
- Release controlled by diffusion through membrane.
- In simplest form, space between an 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- Release controlled by diffusion through polymer matrix.
Basic components of patch
- Drug(s) in a polymer matrix or reservoir
- Penetration enhancers (accelerants) – interact with Stratum Corneum to alter structure e.g. Sodium lauryl sulfate.
- Adhesive – pressure sensitive & compatible with drug and all excipients. Examples; Polyacrylate, polyisobutylene, Polysiloxane.
- Protective release linear – chemically inert & disposable & usually occlusive to prevent loss of volatiles.
- Outer backing laminate-flexible but good tensile strength. Paper, plastic or foil. Examples; polyesters, elastomers, ethylene vinyl acetate (EVA), aluminised plastic laminate.
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.
How to maximise drug delivery
- ) Have drug at its saturation solubility in the vehicle.
(2. ) Use a vehicle which modifies the skin barrier (e.g. Occlusives accelerants).
(3. ) Use a vehicle having a low affinity for the drug (enabling the drug to partition into the SC)
(4. ) Choose a skin site with low thickness.
Adhesive Characteristics
- 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)
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
