Modified Release Preparations Flashcards
What does the acronym CR mean?
Controlled release.
What does the acronym ER mean?
Extended release.
What does the acronym XL mean?
Extended release.
What does the acronym LA mean?
Long-acting system.
What does the acronym SR mean?
Slow or sustained release system.
What does the acronym SA mean?
Slow acting system.
What does the acronym DR mean?
Delayed release.
What does the acronym EC mean?
Enteric coated.
What does the acronym TDS mean?
Therapeutic delivery systems.
What does the acronym ODT mean?
Orally disintegrating tablet.
By what criteria can modified release systems be classified?
- Route of administration (e.g. oral, ocular).
- Type of release (e.g. delayed, sustained).
- Release mechanism (e.g. diffusion, dissolution).
- Technological system (e.g. reservoir, matrix).
For what reasons may modified release systems be developed?
- Enhanced efficacy and tolerance and increased compliance (patient benefit).
- To broaden the product line - extend the patent.
- Delivery for biotherapeutics.
How much can the development of new chemical entities cost?
Often as much as $800m.
What percentage of the cost of developing new drugs is spend on developing new delivery systems?
10%
What factors may change the efficiency of absorption of orally dosed drugs?
- pH – altered ionisation, altered solubility AND degradation – use enteric coats.
- Gastric residence time (~12hrs).
- Intestinal transit.
- Food.
- Absorption window – not necessarily uniform along the whole GIT.
Less drug is used in modified release systems, why is this?
- Drug is delivered locally to the site of action.
* Drug is retained largely at the site of action.
How does use of modified release systems affect the dosage of drugs used?
- Controlled for fixed periods of time.
- Rate and duration specified.
- Reduced dosage compared to conventional systems.
- Increased efficacy.
How does the use of modified release systems affect compliance?
Compliance is increased as dosage frequency is reduced.
What are the commercial effects of using modified release systems?
- Savings due to better disease management.
- Adding value to generics.
- Market expansion.
- Creating new markets.
What are the potential limitations of modified release systems?
- Oral products subject to physiological variation.
- Increased requirement for excipients.
- Can be expensive.
- Surgical operation may be required for implants.
- Difficulty in shutting off release if required.
If biodegradable excipients are used in modified release systems, what should be taken into consideration?
The toxicity of bi-products.
What physiological variations can orally delivered modified release systems be subjected to?
o Limited duration (12-hour transit).
o Entrapment in tract.
Briefly describe membrane-controlled reservoir systems.
In these systems, the drug is completely contained within a rate-controlling membrane. This allows for constant zero-order release rates to be achieved. This can extend the period of dosing by allowing for release over a substantial period of time.
What are the advantages of using membrane-controlled reservoir systems?
• High level of loading.
• Drug can be a large part of the device (90%).
o Efficient use of materials.
o Allows for the use of low potency drugs (higher doses).
• High release rate is achievable.
o Tune pore size.
o Lower density drugs, larger pores – more release.
What are the disadvantages of using membrane-controlled reservoir systems?
• Fabrication is usually quite expensive.
o Release rates depend upon:
Membrane thickness, area, permeability.
Careful control of variables - increases cost.
o Materials usually expensive.
• Difficult to deliver high molecular weight compounds.
• Generally, have to be removed from site.
• Danger of dose-dumping.
o Damage to membrane.
What release kinetics do membrane-controlled reservoir systems exhibit?
Zero-order.
After the useful lifetime of the device, what period is the device said to have entered?
Exhaustion period.
How may the concentration gradient be held constant to maintain zero-order release in membrane-controlled reservoir systems?
- Use of a drug with limited solubility.
- Formulate drug as a suspension (i.e. saturated solution) inside reservoir.
- Delivery of a small fraction of total drug in the reservoir (i.e. maintain excess).
For zero-order release a constant concentration must be maintained within the device.How is this maintained?
By maintaining undissolved solid in the device.
By what means may reservoir depletion occur in membrane-controlled reservoir devices?
• Loss of drug. o From solution. o Later stages of suspension. • Entry of water. o May dilute liquid fill. o May dissolve solid residue.
With regards to membrane-controlled reservoir systems, what is the lag period?
This is where the concentration in the membrane is less that that at steady state, so it takes time for the concentration to reach the steady state. This often occurs in recently manufactured devices as the drug hasn’t fully penetrated the membrane yet.
With regards to membrane-controlled reservoir systems, what is the burst effect?
This is where the concentration in the membrane is more than it would be at steady state. This is caused by slow diffusion of drug into the membrane during storage, When the drug is administered there is a sharp rise in concentration which is then followed by steady state.
Describe the effects of membrane geometry on membrane-controlled reservoir systems.
Devices may have membranes fit for diffusion on only some of the sides of the device, therefor drug release may only occur through these sides. This can affect the calculations that may need to be done.
For example, a slab has two faces for diffusion so the area value in the calculations must be modified to acknowledge this.
Polymers used for membranes in membrane-controlled reservoir systems are generally hydrophobic, give some examples.
- Ethylcellulose (and insoluble derivates) and hydroxypropyl cellulose.
- Acrylic and methacrylic acid polymers.
- Waxes.
- Copolymers of ethylene and vinyl acetate.
- Silicone derivatives – added flexibility.
Describe microencapsulated reservoir systems.
These are oral pelleted products, small spheres often a few millimetres in diameter. The drug is transported and released from coated pellets, which usually come contained in a capsule shell. The drug release from these formulations is more akin to that of a suspension.
What are the advantages of using microencapsulated reservoir systems?
.- Reduced chance of dose dumping.
- More uniform passage down the GIT.
- Ability to pass through the pyloric sphincter at the bottom of the stomach.
Describe the Spansule capsule system.
This is a microencapsulated reservoir system that features drug release from a group of beads that have coatings of different thicknesses. The beads with the thinnest coating provide the initial dose and maintenance of drug levels at later times is provided by the beads with thicker coating.
Describe multiple-release products/pulsatile release systems such as Minocin MR.
Minocin MR capsules have been formulated as a ‘double-pulse’ delivery system. A portion of the minocycline dose is delivered in the stomach and a second portion of the dose is available for absorption in the duodenum and upper GIT.
Describe Elantan LA Capsules.
These are brown/white or brown/pink capsule containing white ‘micropellets’ of isosorbide mononitrate used for angina prophylaxis. 30% of the drug is released immediately and 70% of the drug follows sustained release over 6-8h.
This allows for a fast onset of sustained action and also allows for a nitrate-low period in each 24h period.
List the possible structures of polymers.
- Linear.
- Branched.
- Cross Linked.
- Star.
- Comb.
- Ladder.
- Semi-ladder.
What are dendrimers?
Dendrimers are highly branched constructs formed from a central core which define their initial geometry. They tend to be spherical and have pores within them which can be used to trap small molecules (drugs).
What different groups may be added to a dendrimer?
- Covalently attached targeting moieties.
- Covalently attached solubilising groups.
- Covalently attached drugs.
What is a homopolymer?
A polymer made up of a single monomer.
What is a copolymer?
A polymer made up of more than one type of monomer.
What different types of copolymer are there?
o Alternating copolymer.
o Random copolymer.
o Block copolymer.
o Graft copolymer – a non-linear block, one polymer with another branching from it.
What does the description monodispersed mean with regards to polydispersity?
Polymer branches of the same length.
What does the description polydispersed mean with regards to polydispersity?
Common polymers, with different branch length.
What is the number average molecular weight?
This is determined by chemical analysis and osmotic pressure.
This can be described as the statistical average molecular weight of all the polymer chains in the sample.
What is the weight average molecular weight?
This is determined by light scattering techniques.
This takes into account the molecular weight of a chain in determining contributions to the molecular weight average.
Give some applications for polymers in pharmaceuticals.
• Packaging. o Tops, bungs, containers. • Viscosity modifiers, suspending and emulsifying agents. • Disintegrants. o Crosslinked polymers. • Coating materials. o One of the main uses, retard drug release. • Gels, wound-dressings. • Polymeric delivery systems: o Membranes and matrices. o Adhesives. Patches. o Nano- and micro-particles. Can get into tissues. o Hydrogels. Gel in a 3D structure that is used to release the drug. o ion exchange resins.
With what characteristics can synthetic polymers be synthesised with?
Polymers can be synthesised with pH-dependent solubility or viscosity, biodegradability or membrane-forming characteristics.
How do enteric coatings work?
For example, enteric coatings are formulated with acidic moieties that prevent breakdown in the acidic environment of the stomach but can be broken down in the small intestine.
