Design of Modified/Controlled Release Dosage Forms

Question 1

Aims of modified release

Answer 1

Improved bioavailability
Designed to release drug slowly after ingestion leading to maintained blood levels
Reduced side-effects related to reduced plasma concentrations and reduced dose
Reduced irritancy
More constant blood levels can bring improved efficacy
Economic savings
More convenient form with the need for less frequent dosing
Repeat action systems designed to give patients two full doses

Question 2

Limitations of modified release

Answer 2

Physiological factors
GI transit time
Lodging of dosage form
Not all drugs appropriate (decreased half life drugs hazardous)
Tolerance
Physical size
Unit cost
Activity must be aligned closely to unit concentration

Question 3

What is the benefit of controlled release?

Answer 3

A dosage form that is able to provide some actual therapeutic control
There is often a desire to achieve zero order release
Temporal control- release over time
Spatial control- only deliver in certain area e.g. colon

Question 4

In practice achieving constant blood levels is very difficult:

Answer 4

Maintenance dose must be released at a precise controlled rate that is in mass balance with drug elimination and at required therapeutic concentration
Physiological conditions often variable
Inter-patient variability in drug absorption

Question 5

What you need to know to make controlled release

Answer 5

The rate limiting step for drug action
The optimal blood concentration curve
Elimination
Dose size
Metabolism- drugs that induce, inhibit or have a high first pass are not suitable

Question 6

Enteric coating

Answer 6

Stops the tablet disintegrating at acid pH
They are used to prevent an unstable active being destroyed, prevent the stomach irritation, and facilitate drug absorption in the GI later in transit to improve bioavailability
Delay relates to gastric residence time

Question 7

Polymers used for enteric coating

Answer 7

Film coating of tablets, granules, hard and soft gelatin capsules
The COOH means they are insoluble in aqueous media at low pH (1-3)
As pH rises, there is a sharp increase in solubility, ideally > pH 5
Delay and significant variability in onset of activity (note gastric emptying can range from 30 minutes to several hours)

Question 8

Enteric coated granules or pellets

Answer 8

Entrapment in a rapidly dissolving hard gelatin capsule or rapidly disintegrating tablet
Eliminates dependence on all or none gastric emptying and dose dumping onto intestinal mucosa
<1mm pellets or granules empty from the stomach with liquids via closed pyloric sphincter

Question 9

Reservoir type- diffusion controlled

Answer 9

Tablet or multi-particulate pellet containing drug
Drug does not diffuse in the solid state
Membrane does not swell
Liquid diffusing in forms a continuous phase

Question 10

Reservoir type- diffusion controlled single unit

Answer 10

Usually compressed tablets
Difference from immediate release form is that the core is not designed to disintegrate, but to dissolve
e.g. lactose, microcrystalline cellulose, dextrose
Soluble fillers are chosen to minimise osmotic effects

Question 11

Reservoir type- diffusion controlled multiple units

Answer 11

Usually coated pellets, ~1mm in a hard gelatin capsule or compressed tablet
No issue with gastric emptying
To achieve pulsatile release, change thickness of coating on half of reservoirs

Question 12

Advantages of diffusion controlled

Answer 12

GI transit is less variable
Less likely to show total dose dumping
Release can be more easily optimised

Question 13

Disadvantages of diffusion controlled

Answer 13

Dose dumping can occur from a single-unit system
Multiunit systems can be difficult to retain in higher GI
Control of polymer membrane coating and its characterisation can be difficult
Filling multi-unit systems into capsules can be a problem because of static build up

Question 14

Soluble and hydrophilic colloid matrices

Answer 14

Monolithic matrix system
Drugs particles dispersed in a soluble matrix
Drug becomes available as the matrix dissolves, swells or swells and dissolves

Question 15

Lipid and insoluble polymer matrices

Answer 15

Monolithic matrix system
Drug particles dispersed in an insoluble matrix
Drug becomes available as the solvent enters the matrix and dissolves the drug particles

Question 16

Soluble matrices

Answer 16

Monolithic matrix system
Drug particles dispersed in a soluble matrix
Excipients used to make a soluble matrix include polyanhydrides and polyorthoesters
Surface erosion with little bulk erosion as drug is solubilised from the degrading surface
Bulk erosion- degrades from interior creating more channels for diffusion of drug out
Dissolution of polymer

Question 17

Lipid and insoluble polymer matrices

Answer 17

Monolithic matrix system
Drug particles dispersed in an insoluble matrix
Fluid dissolves drug particles- not suitable for poorly soluble drugs
Chanelling agents- can be used to leach from the formulation leaving tortuous channels

Question 18

Hydrophilic colloid matrix

Answer 18

Swellable matrices swell and sometimes following gel formation dissolve
Tortuosity and microviscosity control diffusion rate
Diffusion of drug through hydrated polymer fibrils controls release rate

Question 19

Advantages of hydrophilic colloid matrix

Answer 19

Comparatively simple
Cheap and easy to manufacture
Different types of release profile
Can contain a high drug loading

Question 20

Disadvantages of hydrophilic colloid matrix

Answer 20

Release of drug is dependent on two diffusion processes- water in and drug out
Erosion of outer layer complicates release profile
Scale-up can be a problem and need good batch reproducibility of rate controlling excipients

Question 21

Use of nan-sized formulations

Answer 21

Becoming popular for poorly soluble new CNS drugs
Can reduce inter-patient variability
Ca reduce the effect of a fatty diet on increasing oral absorption
Can ensure rapid early absorption, can be very important e.g. in pain control
Using a poorly soluble drug or use of a specific drug salt form it is possible to tailor a modified release form

Question 22

Dissolution controlled systems: using coatings

Answer 22

Drug release is sustained according to the different dissolution rates of the coating around the active ingredient
Rate depends on saturation solubility, concentration of solute in bulk solution, surface area and thickness of the coating

Question 23

Repeat-action dosage form

Answer 23

Repeat action tablet or gelatin capsule
Usually contains 2 or 3 doses of drug- the first to give a rapid onset of action
The second dose is often delayed by use of an enteric coat

Question 24

Pulsatile/repeat release systems

Answer 24

Varying coat thickness or its solubility

Use a number of different size releasing units to prepare tablets

Question 25

Osmotically controlled systems

Answer 25

Driven by the difference in osmotic pressure inside and outside the dosage unit
Require dissolution of drug inside the dosage unit
Convective transport of a saturated drug solution out through a single hole in a semi-permeable membrane
Pumping can be accomplished by inclusion of an expansion layer which swells on contact with water, or due to increased volume of water inside

Question 26

Advantages of osmotically controlled systems

Answer 26

Zero-order release is obtainable
Reformulation is not required for different drugs
Release of drug is independent of environment of the system

Question 27

Disadvantages of osmotically controlled systems

Answer 27

Size of hole is critical
Laser drilling is costly
Need careful control of coating and coat characterisation
Potential for dose dumping
Systems can be very expensive
Quality control is more extensive
Failure of pin hole/system can lead to dose dumping

Question 28

Other ways to tract modify release in oral dosage forms

Answer 28

Ion exchange systems
Ion exchange materials are water insoluble resinous materials containing salt forming groups. The resins are mixed with drug solution to form drug-charged resin which is dried and bound into a tablet
Drug release in situ is stimulated by charged ions in the GI (relies on ions not pH or enzymes)

Question 29

Site specific drug delivery e.g. colon specific

Answer 29

Poor site for drug absorption but large surface area
Interest in local delivery of drugs needed to act there e.g. IBD
Possibility to use bacterial microflora to activate prodrugs and to degrade coatings
Possible to use pH sensitive polymers

Question 30

Limitations of oral modified release drug forms

Answer 30

Physiological factors e.g. pH, enzyme activities, transit times, gastric emptying
Transit can limit time of action
Product characteristics- if they remain intact and become lodged, a high local concentration of drug can cause irritation
Drug half life
MR products usually require a higher total drug content

Question 31

Dissolution controlled systems

Answer 31

Can be drug particles, inert particles coated with drug, a conventional tablet coated with a dissolving film or a drug embedded/dispersed in a slowly dissolving matrix
Can be complex systems e.g. alternating layers of rate controlling coats, groups of beads with different coatings, or can be as simple as leaving out the disintegrant in a tablet formulation

Question 32

OROS technology

Answer 32

ALZA has now applied their technology to 13 products
Uses osmosis to provide precise controlled drug delivery for up to 24hrs, can be used with a range of compounds including poorly soluble or highly soluble drugs, can be used to deliver high drug doses
E.g. Procardia XL for angina or hypertension, Concerta for ADHD