Modified drug delivery

Question 1

What are modified release dosage forms?

Answer 1

preparations where the rate and/or place of release of the active substance is different from that of a conventional-release dosage form administered by the same route.

Question 2

What are the factors affecting design strategy of modified release drugs?

Answer 2

Physiology of GI tract
- gastric emptying time
- intestinal transit time

Physicochemical properties of the drug
- aqueous solubility and stability
- pKa
- partition coefficient
- salt form

Choice of the dosage form
- single-unit dosage form e.g. tablets
- multiple-unit dosage form e.g. granules, microcapsules
- MR dosage forms

Drug release mechanisms
- diffusion of dissolved species
- dissolution of the active drug component

Question 3

What are the types of modified release dosage forms?

Answer 3

inert insoluble or hydrophilic matrices
reservoir systems
erosion controlled formulations
osmotically controlled formulations
ion exchange resins.

Question 4

What are the components of a MR delivery system?

Answer 4

Active drug

Release-controlling agents
- matrix formers e.g. hydrogenated vegetable oils, carnauba wax
- membrane formers e.g. ethyl cellulose, acrylic copolymers (Eudragit), shellac

Matrix or membrane modifier
- channelling agents (e.g. sodium chloride, sugars and polyols) for wax matrices
- solubilizers for hydrophilic matrices

Solubilizer
- e.g. PEGs, polyols, surfactants

pH modifier (inclusion of buffers or counter-ions)

Lubricant
- e.g. magnesium stearate

Glidant
- e.g. talc, colloidal silicon dioxide

Supplementary coatings to extend lag time, further reduce drug release

Question 5

What are the four mechanisms to achieve controlled drug release?

Answer 5

Diffusion-controlled release systems

Dissolution-controlled release systems

Erosion-controlled release systems

Osmosis-controlled release systems

Question 6

What is a diffusion controlled release system? What are the two types?

Answer 6

Transport of dissolved drugs in pores filled with gastric or intestinal fluid or in a solid phase (polymer) by diffusion is the release controlling process.

1) Matrix or monolithic systems
- diffusion occurs in pores located within the bulk of the release unit

2) Reservoir or membrane-controlled systems
- diffusion occurs in a thin water-insoluble film or membrane which surrounds the release unit.

Question 7

What are matrix or monolithic systems? How are they different?

Answer 7

diffusion controlled release system

those with drug particles dispersed in a soluble matrix
- with the drug becoming available as the matrix dissolves or swells and dissolves (hydrophilic colloid matrices)
= swelling causes the drug to diffuse out

those with drug particles dispersed in an insoluble matrix (lipid and insoluble polymer matrices)
- with drug becoming available as a solvent enters the matrix and dissolves the particles e.g. polyvinyl acetate, ethylcellulose.
- solvent entering and dissolution of the insoluble matrix causes swelling that enables diffusion of the drug

Question 8

What is the difference between true gels and viscous matrices?

Answer 8

True gels – forms a cross-linked polymeric structure
= e.g. alginic acid with gelatin

Viscous matrices – simple entanglement without crosslinking
= e.g. HPMC, sodium alginate

Question 9

What are the factors affecting release rate of diffusion controlled release systems?
matrix and monolithic systems

Answer 9

Amount of drug in the matrix

Porosity of the release unit
- void spaces

Length of pores in the release unit (depends on the size of release unit and pore tortuosity)

Solubility of the drug (regulates concentration gradient)

Question 10

What is a reservoir or membrane controlled system?

Answer 10

type of diffusion controlled release system

• a drug reservoir e.g. a tablet or multiparticulate pellet, is coated with a membrane.
• can also be used for transdermal patches

the drug should not diffuse in the solid state. Aqueous medium diffusing into the system and forming a continuous phase through the membrane initiates drug diffusion and release

To allow the drug to diffuse out, the membrane has to become permeable.
The polymer should remain intact for the period of release.

Question 11

What is a dissolution controlled release system?

Answer 11

Release of the drug covered with a slow dissolving coat occurs in two steps:

1. the liquid that surrounds the release unit dissolves the coating (rate-limiting dissolution step)
2. The solid drug is exposed to the liquid and subsequently dissolves.

to achieve a prolonged release based on dissolution of a coating, the tablet is formulated to release the drug in a series of consecutive pulses, i.e. a pulsatile release.

delayed release tablets are also formulated using this mechanism.

Question 12

What is an erosion controlled released system?

Answer 12

Drug release from an erosion system can be described in two steps:

1. Matrix material, in which the drug is dissolved or dispersed, is liberated from the surface of the tablet.
2. The drug is subsequently exposed to the GI fluids and mixed with or dissolved in the fluid.

examples of eroding matrices:
lipids or waxes; polymers that gel in contact with water
e.g. hydroxyethyl cellulose

Question 13

What is an osmotic controlled release system?

Answer 13

Three steps involved in release process:
1. Osmotic transport of liquid into the release unit.
2. Dissolution of drug within the release unit.
3. Convective transport of a saturated drug solution by pumping of the solution through a single orifice or through pores in the semi-permeable membrane.

flow of liquid into the release unit, driven by a difference in osmotic pressure between the inside and the outside of the release unit
- is used as the release-controlling process

Question 14

What are the factors affecting water flow rate and hence drug release rate in osmotic controlled release systems?

Answer 14

Osmotic pressure of the drug solution within the release unit
Drug solubility
Permeability & mechanical properties of the membrane

Question 15

What are the advantages of modified release formulations?

Answer 15

Improved control over the maintenance of plasma-drug concentration

Improved patient compliance
- due to reduction in the number and frequency of doses to maintain the desired therapeutic response.

Reduction in the incidence and severity of localised GI side-effects
- produced by ‘dose dumping’ of irritant drugs.

Cost savings
- due to better disease management

Question 16

What are the benefits of improved control over the maintenance of plasma drug concentration?

Answer 16

Avoidance of symptom breakthrough if the plasma concentration drops below MEC
- e.g. asthma, depressive illnesses.

Maintenance of therapeutic action of a drug during overnight ‘no-dose’ periods
- e.g. management of pain permits improved sleep.

Reduction in the incidence and severity of untoward systemic side-effects related to high peak plasma drug concentrations

Reduction in the total amount of drug administered over the period of treatment.

Question 17

What are the limitations of modified release formulations?

Answer 17

variable physiological factors interfere with the control of drug release and absorption
- GI pH, enzymatic activities, gastric and intestinal transit rates, food and severity of disease

transit rate of MR products along GI tract limits the maximum period for which a therapeutic response can be maintained

drugs with low biological half-lives (e.g. ≤ 1 hour) are unsuitable for incorporating into MR formulations.

unsafe overdosage if the MR product is improperly made and the total drug contained therein is released at one time.

cost is more per unit dose
- however, fewer ‘unit doses’ of an MR formulation should be required.