Lec 12- Reservoir systems

Question 1

Classification

Answer 1

• Modified release dosage forms may be classified according to a number of different criteria
  
  • 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)

Question 2

Controlled-release Mechanism

Answer 2

Question 3

Diffusion-controlled Devices
Membrane-controlled Reservoir Systems

Answer 3

• The drug is totally contained within a rate-controlling membrane
• Allows constant zero-order release rates (rate of drug release is consitent and not dependent on concentration of the drug) to be achieved
• An extended period of dosing
  
  • Release over a substantial period of time

Question 4

Membrane-controlled reservior systems

Advantages

Answer 4

• advantages of choosing a reservoir-type system
  
  • high level of loading
  • drug can be a large part of device (~90%)
    
    • efficient use of materials
    • allows use of low potency drugs (you can use higher doses)
  • High release rates achievable- these are achievable- tune the polymer you have (lower density, open pore-size etc)

Question 5

Membrane-controlled Reservoir Systems: Disadvantages

Answer 5

• Fabrication usually quite expensive
  
  • Release rates depend upon:
    
    • Membrane thickness, area, permeability
    • Careful control of variables - increases the cost
    • Materials usually expensive
• Difficult to deliver high molecular weight compounds- pore size is the limitation (large particle small pore so drug gets trapped)
• Generally, have to be removed from the site
• Danger of dose-dumping
  
  • Damage to membrane

Question 6

Membrane diffusion

Answer 6

• Diffusion: flow from a more concentrated to a less concentrated region
• The release is dependent on diffusion through the membrane
• Donor compartment (INSIDE THE DEVICE) and Receiver compartment (Outside)
  
  • With concentration being in the donor the drug will flow down the concentration gradient going from high to low or donor to the receiver
    *

Question 7

Membrane Diffusion
Fick’s First Law

Answer 7

• Flux (J) = Mass flow across membrane per unit time per unit area
• Change in mass / Area x change in time
• Use bottom left equation

Question 8

Control of drug release

Answer 8

Where

• dMt/dt= Rate of drug release (mass/time)
• A = Membrane surface area
• D = Diffusion Coefficient of drug in membrane
• K = Partition Coefficient of drug in membrane
• Cs = Concentration of drug in the donor compartment
• Cr = Concentration of drug in the receiver compartment
• h = Membrane thickness

Question 9

Membrane diffusion

Control of zero order release

Answer 9

• Under sink conditions (Cs>>Cr)- Much more drug in the donor, large gradient
  
  • Use a large volume (more than needed to dissolve)
  • The body always have sink conditions
• dM/dt = constant… when concentration gradient is held constant

Question 10

Membrane Diffusion
Zero Order Release

Answer 10

• Graph on the right is drug release rate, the release rate is stable

Question 11

Membrane Diffusion
Control of Zero Order Release

Answer 11

• Most of the time, the concentration gradient is held constant for a defined ‘life-time’ e.g. Ocusert eye inserts releases the drug for up to 7 days with zero-release kinetics (while there are sink conditions).
• Concentration gradient may be held constant to the main zero-release by:
  
  • Use of a drug with limited solubility
  • Formulate drug as a suspension (i.e. saturated solution) inside the reservoir
  • Delivery of a small fraction of total drug in the reservoir (i.e. maintain excess)

Question 12

Duration of Constant Release Rate

Answer 12

• For zero-order release
  
  • a constant concentration within the device must be maintained
    
    • Lasts as long as there is undissolved solid within reservoir
    • Eventually all solid dissolves and release rate falls
• This is the useful “life-time” of the device

Question 13

Duration of Constant Release Rate

Answer 13

• We can quantify the Duration of Constant Release t_infinity
• Mass of drug in the device at end of zero order period = Cs V
• The initial mass of drug = M₀
• Mass of drug delivered = M0 – Cs V
• NB- don’t have to learn the equations

Question 14

Membrane-controlled Reservoir Systems-Release Profile

Answer 14

• Green line= zero order no change in release rate- steady state
• • Red= Exhaustion- release rate starts to decline
    *

Question 15

Non-steady state release

Answer 15

• Concentration in the membrane is less than that at steady state
• The recently manufactured device may take time to release the drug
• Slow release period, then the release rate increases until it reaches a steady state

Question 16

Storage effects lag period

For new devices

Answer 16

• In the new device, the concentration gradient is much lower due to the fact that it takes time for the drug to reach a steady state- we have not got zero order release yet as sink conditions have not been met

Question 17

Storage effects

Burst effects

Answer 17

• Burst effect- fast release
• As the drug on the surface is lost the release of the drug slows down as the remainder of the drug has to travel through the release controlling membrane, this slowing continues until a steady state (zero-order) release rate has been achieved

Question 18

Non-steady state release

Burst effect

Answer 18

• Concentration in the membrane is more than that at steady state
• BURST EFFECT
• Opposite to lag period
• Older device
• Due to long storage, drug starts to penetrate the reservoir membrane and cover the surface of the formulation- therefore there is no barrier between the drug and patient
• This leads to a steep increase in the mass of drug release

Question 19

Non-steady state release storage effects

Answer 19

• Time to reach steady state depends upon
• D (diffusion co-efficient- how fast the drug diffuses through the membrane)- the greater this co-efficient the faster the release
• h (membrane thickness- smaller the thickness faster the time to burst effect)- general release will be faster with thinner membranes
• Not on drug loading- DOESN’T depend on how much drug is in the device

Question 20

Release from Devices
Effect of Geometry

Answer 20

• We have drug in the layer in the middle with the release layers at the top and bottom
• Use the same equation as before
• Consider change in the area

Question 21

Membrane Diffusion
Polymers

Answer 21

• Polymers used for membranes are generally hydrophobic and include
• We make sure that the drug is insoluble in the polymer- if it were then the thickness of the membrane would change as time went on- this means that we would lose the zero order release rate that is required
  
  • ethylcellulose (and insoluble derivates) and hydroxypropyl cellulose
  • acrylic and methacrylic acid polymers
  • waxes
  • copolymers of ethylene and vinyl acetate
  • silicone derivatives- used when the formulation needs to be flexible