Week 11 - Modified Drug Release Flashcards
Why do we use MR (modified drug release) over IR (immediate release)
We want to achieve “steady state” plasma conc.
(remain in therapeutic window with NO fluctuations)
- achieved by repetitive administration of IR
OR
- use MR drugs
IR drugs
- have frequent dosing intervals as drug conc. fluctuates over time = need to be administered often
- have short half lives = frequent dosing REQUIRED = adherence issues, may forget etc.
MR drugs
- drug is released over period of time to meet therapeutic needs
- drug can be targeted i.e. specific location (organ, tissue)
- have reduced frequency of dosing = more convenient
What are the advantages + disadvantages of MR
- Less fluctuations (i.e. peaks / troughs between MTC and MEC)
- have steady state plasma conc. - Improved compliance
- less frequent dosing - Efficient use of drug
- lower overall amount of drug used - Have better safety margin
- avoid under + over-treatment - Reduction in healthcare cost
- less monitoring, less dispensing, shorter treatment time
DISADV: risk of dose dumping (can be toxic)
List the Modified drug release forms
- Delayed Release (DR)
- Extended Release (ER) = slow drug release over period of time
2a. Sustained Release
2b. Prolonged Release
2c. Controlled Release
What is the difference between Immediate Release (IR), Repeat Action (RA), Sustained Release (SR) and Delayed Release (DR)
DR - drug is NOT released immediately after administration, released at a later time
IR - drug is ALL released immediately after administration
SR - INTIAL drug release after administration (to provide therapeutic dose) THEN slow gradual release over period of time
- gradual so plasma conc. remains within therapeutic region
RA - INITIAL dose released after administration THEN 2nd / 3rd dose released at later INTERVALS
- mimics taking tablet every few hours (but combined into 1)
- results in fluctuation as next dose is only released when 1st dose is gone
What drugs are suitable for MR
Class 1 drugs = ↑ solubility and ↑ permeability = BEST (wanted)
Class 2 = ↓ solubility and ↑ permeability = acceptable
Class 3 = ↑ solubility and ↓ permeability
Class 4 = ↓ solubility and ↓ permeability = WORST
- Drugs with short half life (t1/2) ~ 2-8 hours
- very low t1/2 = drug is cleared very quickly - Drug has high therapeutic window
- Drug has moderate potency
- needs small doses ~ avoid toxicity if dose dumping occurs - Drugs that are stable + absorbed through GIT
- pellets leave stomach rapidly compared to single dose units
List some MR products
- Potassium Chloride ER Capsules - treta hypokalaemia
- microencapsulation
- KCl dissolves within microcapsule as fluid passes through membrane + dissolves across membrane - Morphine ER
- MST Continus (film coated tabs), Zomorph (pellets), MXL (hard gelatine capsules)
- for serve pain + cancer patients
MST Continus Tablets - dissolution of the aliphatic alcohol + dissolution of drug through hydrated cellulose determine rate of release
MST Continus Suspension Granules - morphine found to ion exchange resin beads
- morphine is displaced by Na+ and K+ ions = drug released
Zomorph - pellets in a capsule shell
- drug diffuses across the ethylcellulose coat (coat is destroyed by chewing)
MXL Capsules - powder morphine + hydrogenated veg. oil (wax matrix) are encapsulated
- drug release when water enters
What are the common drug release systems for oral delivery
- Single-unit
- e.g. tablets, capsules, matric tablets, coated tablets - Multiple-unit
- e.g. granules, microcapsules, capsules, beads
- microcapsules = coating each indiviual microscopic particle - MR
- reservoir system, insoluble matrix, hydrophilic matrix, osmotically controlled
How is MR formulations achieved
- Use coatings
- use specific polymer so coating erodes at specific pH (within parts of body) - Embed drug in wax or plastic matrix (polymer)
- Microencapsulation
- coating each individual microscopic particle - Chemical binding to ion-exchange resin
- electrostatic interaction between drug + polymer - Osmotic pump
- controls release by controlling the pressure inside formulation
What controls drug release
- Dissolution rate of drug
- Drug solubility to diffuse out of formulation + be absorbed
Drug Release Process:
1. Hydrate system
= polymer swells forming hydrocolloid OR dissolution channel
2. Water diffuses into system (through channel)
3. Dissolution of drug
4. Dissolve drug diffuses out of system + is absorbed
= drug released from its formulation
What is the MoA for ‘Matrix’ drug release system
Matrix = diff. polymers are used to control release of drug
- 2 types of matrix: WAX and HYDROPHILIC
- Drug is uniformly distributed in matrix
- matrix contains “release controlling agents” - Drug is released near surface of the tablet (over a period of time)
- Over time rate of drug (in system) declines as it diffuses out
- drug deep in matrix takes longer to come out
CAN’T have 0 order reaction with matrix, as this would mean rate is constant (straight line) doesn’t change
WAX:
1. Mix drug with wax (wax = HYDROPHOBIC matrix)
- wax contains channeling agents (water soluble e.g. salts, sugars) to encourage dissolution + diffusion
- hydrophobic agent needs to be stable at 37ºc
- e.g. hydrogenated veg. oil, caster oil, soya oil
2. When wax comes in contact with aqueous = channeling agent dissolves forming porous, capillary channel
- allows water to enter + soluble drug
- allows drug to diffuse out of wax + be absorbed
- more channeling agents = ↑ rate of release
3. Granulation steps
4. Tableting (+ coating if needed)
HYDROPHILIC
1. Drug mixed with hydrophilic colloid, release modifiers + lubricant
2. Hydrophilic colloid swells in contact with water = hydrated matrix formed (hydrogel)
3. Hydrated matrix controls diffusion of water into matrix + diffusion of drug out
- outer layer of matrix erodes (when become more dilute) = ↑ SA = ↑ drug release
What is the MoA for ‘Reservoir’ drug release system
Reservoir = have drug in core, core is coated with membrane that controls release
- Have a rate controlling membrane
- permeability of membrane controls release of drug
- more permeable = ↑ release - Alter rate of release by changing thickness of membrane
- thicker membrane = ↓ rate
CORE contains:
- API (drug)
- Filler
- Solubiliser
- Lubricant
COATING contains:
(if coating fails = dose dumping)
- Membrane polymer
- should NOT swell, erode etc. needs to remain intact / stable
- e.g. ethyl cellulose or shellac
- Plasticiser
- makes drug more soluble
What is the MoA for ‘Osmotic pump’ drug release system
Osmotic pressure is used to generate a constant rate of drug release
Elementary Osmotic Pump:
1. Drug is in core (core solubilises in presence of H2O)
- core also has salt inside = H2O enters
2. Core is coated with cellulose acetate (semi-permeable membrane)
- and agent which prevents swelling
3. As H2O enters = core dissolves + hydrostatic pressure ↑
- when pressure builds up drug released through fine hole at the top (of coating)
Advantages:
- Precise release (fine hole at top)
- Deliver drug to 0 order (constant rate of delivery / same amount delivered per unit time)
What is the MoA for ‘Microencapsulation’ drug release system
- Coating surface of drug particles with polymer (via spraying) to slow down H2O penetration = ↓ dissolution rate
What is the MoA for ‘Ion Exchange Resins’ drug release system
- Ionised drug binds to oppositely charged, insoluble resin
- electrostatic interaction occurs
- resin = 1-2mm beads
- Drug-resin complex is milled = get smaller particles
- Small particles are packed into capsule, tablet or suspended in liquid
How is drug released:
- In GIT the electrolyte conc. may be high = drug is exchanged for another ion
- Na+ displaces compound = drug released
Adv: ↓ risk of dose dumping
