Modified Release Preparations Flashcards
(130 cards)
1
Q
What does the acronym CR mean?
A
Controlled release.
2
Q
What does the acronym ER mean?
A
Extended release.
3
Q
What does the acronym XL mean?
A
Extended release.
4
Q
What does the acronym LA mean?
A
Long-acting system.
5
Q
What does the acronym SR mean?
A
Slow or sustained release system.
6
Q
What does the acronym SA mean?
A
Slow acting system.
7
Q
What does the acronym DR mean?
A
Delayed release.
8
Q
What does the acronym EC mean?
A
Enteric coated.
9
Q
What does the acronym TDS mean?
A
Therapeutic delivery systems.
10
Q
What does the acronym ODT mean?
A
Orally disintegrating tablet.
11
Q
By what criteria can modified release systems be classified?
A
- 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).
12
Q
For what reasons may modified release systems be developed?
A
- Enhanced efficacy and tolerance and increased compliance (patient benefit).
- To broaden the product line - extend the patent.
- Delivery for biotherapeutics.
13
Q
How much can the development of new chemical entities cost?
A
Often as much as $800m.
14
Q
What percentage of the cost of developing new drugs is spend on developing new delivery systems?
A
10%
15
Q
What factors may change the efficiency of absorption of orally dosed drugs?
A
- 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.
16
Q
Less drug is used in modified release systems, why is this?
A
- Drug is delivered locally to the site of action.
* Drug is retained largely at the site of action.
17
Q
How does use of modified release systems affect the dosage of drugs used?
A
- Controlled for fixed periods of time.
- Rate and duration specified.
- Reduced dosage compared to conventional systems.
- Increased efficacy.
18
Q
How does the use of modified release systems affect compliance?
A
Compliance is increased as dosage frequency is reduced.
19
Q
What are the commercial effects of using modified release systems?
A
- Savings due to better disease management.
- Adding value to generics.
- Market expansion.
- Creating new markets.
20
Q
What are the potential limitations of modified release systems?
A
- 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.
21
Q
If biodegradable excipients are used in modified release systems, what should be taken into consideration?
A
The toxicity of bi-products.
22
Q
What physiological variations can orally delivered modified release systems be subjected to?
A
o Limited duration (12-hour transit).
o Entrapment in tract.
23
Q
Briefly describe membrane-controlled reservoir systems.
A
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.
24
Q
What are the advantages of using membrane-controlled reservoir systems?
A
• 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.
25
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.
26
What release kinetics do membrane-controlled reservoir systems exhibit?
Zero-order.
27
After the useful lifetime of the device, what period is the device said to have entered?
Exhaustion period.
28
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).
29
For zero-order release a constant concentration must be maintained within the device.How is this maintained?
By maintaining undissolved solid in the device.
30
By what means may reservoir depletion occur in membrane-controlled reservoir devices?
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• Loss of drug.
o From solution.
o Later stages of suspension.
• Entry of water.
o May dilute liquid fill.
o May dissolve solid residue.
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31
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.
32
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.
33
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.
34
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.
35
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.
36
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.
37
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.
38
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.
39
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.
40
List the possible structures of polymers.
* Linear.
* Branched.
* Cross Linked.
* Star.
* Comb.
* Ladder.
* Semi-ladder.
41
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).
42
What different groups may be added to a dendrimer?
* Covalently attached targeting moieties.
* Covalently attached solubilising groups.
* Covalently attached drugs.
43
What is a homopolymer?
A polymer made up of a single monomer.
44
What is a copolymer?
A polymer made up of more than one type of monomer.
45
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.
46
What does the description monodispersed mean with regards to polydispersity?
Polymer branches of the same length.
47
What does the description polydispersed mean with regards to polydispersity?
Common polymers, with different branch length.
48
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.
49
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.
50
Give some applications for polymers in pharmaceuticals.
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• 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.
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51
With what characteristics can synthetic polymers be synthesised with?
Polymers can be synthesised with pH-dependent solubility or viscosity, biodegradability or membrane-forming characteristics.
52
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.
53
Describe the purity of natural polymers.
These often vary in purity as they are derived from natural sources and may contain microbiological contamination.
54
What is often requires to control release from natural polymers?
Crosslinking.
55
What can natural polymers be made from?
* Polypeptides and proteins – albumin and gelatine.
| * Polysaccharides – starch, chitosan.
56
By what two terms can biodegradable polymers be classified?
They can be classified as either bulk-eroding or surface eroding systems.
57
By what factors can polymer degradation be affected?
• Structure and composition.
• Physical and physicochemical (chemistry) factors.
• Purity.
o Presence of ionic groups, unexpected units or chain defects.
o Presence of low-molecular-weight compounds.
• Molecular weight and distribution.
• Morphology – SA. – bigger particle = greater SA.
• Processing conditions.
• Sterilization process and storage history.
• Shape – same as morphology.
• Site of implantation.
58
Polylactide and Polyactide-co-Glycolide are biodegradable polymers which fall under what classification?
Bulk eroding.
59
What monomers are used to make polylactide and polylactode-co-glycolide?
Lactic acid and glycolic acid.
60
Why are lactic acid and glycolic acid good monomers for drug delivery polymers?
Lactic acid and glycolic acid are good monomers to make a polymer for drug delivery as they are natural products that are compatible with the body.
61
What are the advantages of using polylactide and polylactide-co-glycolide as polymers for pharmaceutical systems?
* Long, safe history – reliable.
| * Biodegrades to natural moieties.
62
What are polylactide and polylactide-co-glycolide polymers currently used for?
They are currently used as sutures, bone implants and screws, and as depot formulations.
63
How are polylactide and polylactide-co-glycolide usually formulated and how are these formulations usually administered?
These polymers are usually formulated as microspheres that are administered by inhalation, injection, or as part of implantable devices; not usually orally.
64
How can PLA and PLGA polymer degradation rate be controlled?
• Molecular weight – different grades.
• Polymer composition (co-polymer ratio).
o Hydrophobicity, crystallinity, glass transition.
• Particle size, shape, morphology, and loading.
• Incorporated drugs have the potential to modify degradation rates.
65
What three phase mechanism was proposed for the degradation of PLGA?
1. Initial rapid decrease in molecular weight with no soluble monomer formation.
2. Decrease in molecular weight with rapid mass loss and formation of soluble products.
3. Formation of soluble monomer resulting in complete polymer degradation.
66
Give an example of a surface-eroding polymer used in pharmaceutical systems.
Polyanhydrides.
67
What are cellulose derivative polymers?
Cellulose derivatives are polysaccharides formed into hydrophilic matrices. They are a popular biomaterial.
68
Give some examples of cellulose derived polymers.
* HPMC.
* HEC.
* HPC.
* MCC.
69
What are the most common modified release systems on the market?
Monolithic systems.
70
Why are monolithic systems the most common modified release system on the market?
This is due to their ease and economics of production.
71
How can monolithic systems for modified release be further classified?
They can be classified as diffusion systems.
72
Describe how the drug is dispersed within a monolithic system.
In a monolithic system, the drug is uniformly dispersed within a water-insoluble matrix.
73
What percentage drug concentration is classified as a simple monolithic dispersion in a monolithic system?
0-5%.
74
How is a drug concentration of 0-5% described in a monolithic system?
As a simple monolithic matrix.
75
What percentage drug concentration is classified as a complex monolithic dispersion in a monolithic system?
5-20%.
76
How is a drug concentration of 5-20% described in a monolithic system?
As a complex monolithic dispersion.
77
What percentage drug concentration is classified as a monolithic matrix system in a monolithic system?
>20%.
78
How is a drug concentration of >20% described in a monolithic system?
As a monolithic matrix system.
79
Why is there little chance of dose dumping with a monolithic system?
With monolithic systems there is little to no danger of dose dumping; the drug is held by a matrix within it, rather than an outside ‘container’.
80
What does release rate from a monolithic system depend on?
The release rate from a monolithic system depends on matrix, loading, and geometry of the system.
81
The release rate from monolithic systems continuously decreases as time goes on, why is this?
The release rate falls because as dissolution goes on, the interface for dissolution recedes. This leads to an increased path length that the drug molecule has to follow before it leaves the dosage form.
82
When release profiles from monolithic systems are linearised and the R^2 value is close to ), what does this mean?
That the release is monolithic.
83
How does increasing the loading of drug into the system affect the rate of release from monolithic systems?
Increased loading increases the rate of release.
84
Describe the release from complex monolithic dispersions.
These are dispersions with 5-20% drug loading. Depletion of drug near surface level leaves cavities in the matrix. These cavities fill with external fluid leafing to water-filled pores. This provides rapid by-pass of the diffusional barrier through the matrix.
These pores are not connected however they do increase the overall permeability at later times.
85
Describe the release from monolithic matrix systems.
These are systems with >20% drug loading, where particles are in contact with one another. Depletion of drug leaves cavities in the matrix, these cavities fill with external fluid (water), and this provides rapid by-pass pores. These pores are connected to form continuous channels and these channels increase overall permeability at later times. Much of the drug is released by diffusion through channels.
86
Monolithic matrix systems are useful for the delivery of what type of drugs?
These systems are useful for the delivery of poorly diffusible drugs.
87
How are monolithic systems prepared?
Their preparation is simple, including the mixing of matrix media with drug and other excipients (as we did in the lab).
88
What are monolithic systems often made from?
These systems can be made from inert (insoluble) polymers and lipophilic compounds (waxes instead of polymers).
89
Give some examples of inert polymers used in the preparation of monolithic systems.
* Polyvinylchloride.
* Polyethylene.
* Ethylcellulose.
* Acrylic resins.
90
Give some examples of lipophilic compounds used in the preparation of monolithic systems.
* Hydrogenated vegetable oil.
| * Mycrocrystalline wax.
91
Channelling agents are sometimes used in monolithic systems, what are they?
This channelling agent is a highly soluble material, such as povidone, which dissolves very quickly, leaving pores for the drug to be released through.
The dissolution of both the channelling agent and the drug occurs simultaneously.
92
Why are monolithic matrix patches easier and cheaper to make than other transdermal patch technologies?
These preparations are easier/cheaper to make than other transdermal patch technologies as the drug/excipients are mixed with the adhesive of the patch.
93
Describe the deponit transdermal patch technology.
This is a transdermal patch system that combines the characteristics of monolithic and reservoir patches. This can be used to provide a matrix system with zero order release kinetics.
Deponit is described as ‘a reservoir gradient-controlled matrix system’. It features a multi-layered matrix holding GTN in a concentration gradient. The matrix is a lattice of fixed lactose crystals to which GTN molecules are adsorbed. This gives a high degree of control over delivery.
94
What is osmosis?
Osmosis is the flow of water through a semi-permeable membrane from a lower to a higher concentration of solute.
95
Outline the concept of osmotic pump systems.
Concentration much higher inside so as water moves in through the semi-permeable membrane, the drug moves out through the orifice.
96
Are osmotic pump systems affected by physiological parameters?
Drug release from these systems is independent of pH and other physiological parameters (gastro-intestinal motility) to a large extent.
97
Describe the full release profile of osmotic pump systems.
Lag time as the device hydrates. Steady release state, zero order. Exhaustion period.
98
Which design variables can be altered to change the properties of an osmotic delivery system?
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• Membrane permeability.
o Nature of polymer.
• Surface area of device.
• Membrane thickness.
o Weight and density.
• Osmotic pressure.
o Nature of osmotic agent.
• Drug solubility or concentration.
• Release orifice.
o Size, number.
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99
What are the advantages of osmotic delivery systems?
* Zero release order is possible.
* Release of drug is independent of the external environment or physiological conditions.
* Reformulation is not required for different drugs.
* Lower risk of dose dumping compared to reservoir systems.
* Possibility of increased stability due to coating.
100
What are the disadvantages of osmotic delivery systems?
• Systems can be expensive.
o Precise drilling of hole.
o Semi-permeable membrane (e.g. polymers of cellulose acetate).
• Technology costs a premium to buy from the creators.
• Quality control is more extensive than for conventional systems.
o Correct size orifice – laser drilled hole.
101
Describe the elementary osmotic pump (oros) system?
. The drug is mixed with water-soluble core material and this core is surrounded by a water-insoluble semi-permeable membrane. The core may be an inert salt, water soluble polymer, or the drug itself (if saturated solution, it must generate sufficient osmotic pressure).
Water molecules diffuse through into the core through membrane to form a concentrated solution. Then, the drug is pushed out of the pre-drilled orifice.
102
Describe the push-pull osmotic pump system.
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This is a modification of the elementary osmotic pump to include a swelling membrane which pushes the drug out of the system.
Drug layer (Pull) contains drug and osmoagent (osmogene) while the push layer contains polymeric osmotic agent. After coming in contact with the aqueous environment, polymeric osmotic layer swells and pushes the drug layer, thereby delivering the drug in the form of a fine dispersion via the orifice.
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103
What types of drug is the push-pull osmotic pump system used for?
Poorly water soluble drugs.
104
Give some examples of a push-pull osmotic delivery system.
* Adalat LA.
| * Ditropan XL.
105
Describe the Adalat LA push-pull osmotic lump system.
Adalat LA consists of a semipermeable cellulose acetate coating, swelling hydrogel layer of polyoxyethylene glycol and HPMC (push layer). The drugs are contained within HPMC and PEG (pull layer).
106
What are the advantages of using a push-pull osmotic pump system?
* Maintains steady drug release.
* Helps release poorly soluble drugs.
* Helps release drugs not compatible with certain excipients.
107
Describe the alzet minipump system.
These are miniature, implantable pumps used for research in laboratory animals. They are used to continuously deliver drugs, hormones, and other test agents at controlled rates from one day to four weeks without the need for external connections or frequent handling. This eliminates the need for repeated night-time or weekend dosing.
108
Describe swelling controlled release systems.
Absorption of water from external environment causes the outer layer to swell, which allows the drug to be release.
109
In swelling controlled release systems, what does drug release depend on?
• Rate of water uptake.
o Porosity.
o Nature of polymer.
• Diffusion coefficient of the drug.
110
What are the advantages of using swelling controlled release systems?
* Comparatively simple concept.
* Easy to manufacture.
* Cheap excipients.
* Erodible – no shell in stool.
111
What are the disadvantages of using swelling controlled release systems?
• Release is dependent on 2 processes.
o Penetration of water through hydrated matrix.
o Diffusion of drug through matrix.
• If the outer layer erodes, there can be complicated kinetics.
112
What materials can be used to make swelling controlled release systems?
• Hydrophilic colloid matrix systems.
o Hydroxypropylmethylcellulose (high grades).
o Sodium carboxymethylcellulose.
• Hydrogel.
o Hydrophilic polymer with water-soluble drug.
e.g. poly(hydroxyethyl methacrylate) and theophylline.
o Diffusion in gel is low but increases as water enters.
113
Describe pH controlled release systems?
These systems generally remain intact in the stomach but will dissolve at higher pHs along the GI tract. Coating materials are usually weak acids that remain undissociated at low pH but ionise at pH>5.
114
Give some examples of enteric coating polymers.
• Cellulose acetate phthalate (CAP).
o Oldest, pH>6.
o Susceptible to hydrolytic degradation.
• Polyvinyl acetate phthalate (PVAP), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS).
• Acrylic acid copolymers are now widely used.
o Methacrylic acid - methyl/ethyl methacrylate copolymers (Eudragit).
115
Explain the concept of chronotherapeutic drug delivery.
The human body follows a certain pattern of activity during the day, known as the circadian rhythm or more commonly the ‘body clock’. Taking this into account, formulation scientists can create delivery systems with timed release to coincide with the bodies rhythms.
116
Which drug may be delivered at night for ischaemic heart disease? Why?
o Anti-anginal agents, Anti-hypertensives, Anti-arrthymics, anticoagulants.
o Reduce morning morbidity and mortality.
117
Which drugs may be delivered at night for asthma? Why?
o Bronchodilators.
| o Reduce nocturnal symptoms.
118
Which drugs may be delivered at night for arthritis? Why?
o Anti-inflammatory agents.
| o Reduce early morning symptoms.
119
Which drugs may be delivered at night for sleep problems? Why?
o Hypnotics.
| o Reduce early waking.
120
Which drugs may be delivered at night for Parkinson's disease? Why?
o Anti-Parkinson agents.
To reduce early morning tremors.
o Anticholinergics.
To reduce nocturnal symptoms.
121
Which drugs may be delivered at night for pain? Why?
o Analgesics.
| o To reduce night time awakening.
122
Which drugs may be delivered at night for HIV? Why?
o Antivirals.
| o To replace midnight dosing.
123
How can site specific delivery of medicines for inflammatory bowel disease be useful?
Site specific delivery can be useful in the administration of medicines for inflammatory bowel disease as it allows for delivery right to the site of action, rather than systematic drug delivery which may have a slower onset of therapeutic action.
124
Describe the Covera HS drug system.
This formulation contains verapamil at either 180 mg or 240 mg. It mimics the body’s typical 24 hour circadian variations in blood pressure and heart rate.
125
The Covers HS system is taken at night, what affect does this have?
* Gives slow release at night.
| * Peak concentrations in the early waking hours when blood pressure and heart rate are maximal.
126
Describe the PulsinCap pulsed-release dosage form.
In this formulation the drug is held within a hard shell capsule which is insoluble. The drug is sealed with a hydrogel plug and a water soluble cap covers the plug.
When the capsule is swallowed, the cap dissolves, the hydrogel plug swells and at pore-determined times the swollen plug is eliminated, and the drug is released as GIT fluids enter the capsule.
127
In the Pulsincap pulsed release system, what is the plug made from?
The plug is made of permeable and swellable polymers (e.g., polymethacrylates), erodible compressed polymers (e.g., hydroxypropylmethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polyethylene oxide), congealed melted polymers (e.g., saturated polyglycolated glycerides, glyceryl monooleate) and/or enzymatically controlled erodible polymers (e.g., pectin).
128
How can external control of drug release be achieved?
• Magnetic-activated devices.
o Use magnetic field.
• Iontophoresis-activated devices.
o Use electrical current to modulate diffusion of a charged molecule across membrane (e.g. skin).
• Ultrasound-activated devices.
o Use ultrasonic energy to trigger delivery from polymer.
129
Give examples of disintegrant excipients.
Croscarmellose sodium, sodium starch glycolate, crospovidone.
130
Explain how salt forms of drugs can increase solubility and hence improve dissolution.
A salt form of a weak acid can increase its solubility in acidic media. A salt form of a weak base can increase its solubility in basic media. This increased solubility increases the amount of drug that is able to be absorbed from the solution.
