controlled drug release (MR opioids) Flashcards
drug delivery systems that have no control of drug release
tablets capsules solutions suppositories inhalers
What is a sustained release formulation?
formulations that should prolong biological activity
slow release of drug over a time period
may or may not be controlled release
What is a controlled release formulation?
formulation that control the rate at which the therapeutic agent is released into the body
perfectly zero order release
drug released constantly over time irrespective of concentration
2 types of systems that give control to drug release
sustained release
controlled release
graph for zero order release (controlled release)
straight line through origin
drugs that benefit from zero order/controlled release
anti-inflammatories
24hr release
eg. naproxen
advantages of controlled release dosage forms
- reduced frequency of dosage
- more effective utilisation of the therapeutic agent
- lower incidence of side effects
- improved control of disease state
problems/dangers with conventional products (not controlled release)
need to stay within the therapeutic window
- between the MEC and MSC
- plasma conc might go below the MEC
- could go above MSC (s/e)
coltrolled release time curve
- one repeat action dosage form containing 2 doses
- 1st is IR to reach the therapeutic window
- 2nd is a maintenance dose
disadvantages of controlled release dosage forms
- more difficult and expensive to manufacture
- potentially fatal is there is a problem with the manufactured product (larger amt of drug)
- prolongation of s/e after admin
- if the drug is elimiated at low rate there is a damger of accumulation
- potentially dangerous for drugs that have a narrow therapeutic window
principles for obtaining controlled/extended release preparations
utilisation of chemical reactions
- formation of insoluble salts
- prodrugs
utilisation of the pharmacokinetic phase
- prolongation of absorption
- prolongaiton of metabolism (enzyme inhibition)
- prolongation of excretion (competitive interaction in renal tubules)
3 types of diffusion controlled drug delivery systems
reservoir
matrix
miscellaneous
RESERVOIR diffusion controlled systems
diffusion controlled by
- a membrane (transdermal systems)
- > made from polymers
- OR a coating (tablets, patriculates, granules)
MATRIX diffusion controlled systems
homogenous systems (monolithic)
heterogenous systems (granular)
MISCELLANEOUS diffusion controlled systems
osmotically controlled systems
example of reservoir system
Flamel’s Micropump technology
- 5,000 - 10,000 microparticles
- microparticles are 200-500 microns in diameter
- in a tab/capsule
- released into stomach and go to small intestine
- each microparticle is a delivery system
- drug released by osmotic pressure over 24hrs
- release is pH independent
- suitable for drugs with short half lives
desscribe diffusion controlled release RESERVOIR system
water insoluble polymeric material encases a core of drug
drug will partition into the membrane and exchange with the fluid surrounding the particle/tablet
additional drug will enter the membrane, diffuse to the periphery and exchange with the surrounding media
3 types of formulations of reservoir systems
implantable
oral
transdermal
formula for the drug delivery rate
dM/dt = ADK (*C/l)
dM/dt = drug delivery rate
A = area of coating
D = diffusion coefficient
K = partition coefficient
l = thickness of the coat (diffusional pathlength)
C = conc of drug in core
triangle C = conc diff across the coating
What parameter to decrease in the formula to extend the release?
decrease the thickness of the coat
describe MATRIX diffusion controlled delivery
- powder drug homogenosly dispersed through a matrix tablet
- drug dissolves in the polymer matrix and diffuses out from the surface of the matrix
- as drug is released the distance for dissusion becomes greater
- boundary between drug and matrix recedes into tab
what is total conc of drug Co greater than (matrix system)
total conc of drug Co (dissolved and dispersed is greater then than the solubility of the drug in the matrix Cs
What does the Higuci equation depend on?
the rate of drug release was dependent on drug diffusion and not on the rate of drug dissolution
What is A in the Higuchu equation?
total concentration dissolved and undissolved drug in the matrix
What is Cs in the Higuchi equation?
solubility or saturation concentration of drug in the matrix
dh and dQ
dh - drug passes out of homogenous matrix the boundary of drug moves to the left by an infinitesimaldistance dh
dQ - infinitesimal amount of drug released
Higuchi equation
dQ/dt = sq/ (ADCs/2t)
How to alter rate of drug release (dQ/dt)?
- inc/dec the solubility of the drug in the polymer
- inc/dec the total concentration of drug
- altering the crystallinity of the polymer (amorphous has higher rate of drug release)
describe heterogenous matrix controlled system
- release of a drug from a granular matrix
- simultaneous penetration of the durrounding liquid
- dossolution of drug
- leaching out of the drug through interstitial channels/pores
What type of matrix is a granule?
porous/heterogenous
not homogenous
What extra needs to be accounted for in the diffusion equation for a heterogenous matrix system?
volume and length of the opening in the matrix
Higuchi equation for heterogenous matrix drug delivery
Q = sq/ (De/tor) (2A - eCs) (Cst)
porosity (e) in heterogenous matrix system
posority is the fraction of the matrix that exists as pores or channels into which the surrounding liquid can penetrate
porosity of the matrix following complete extraction of the drug
What does tortuosity account for?
for an increase in path length of diffusion due to branching and bending of the pores
inc tortuosity decreased the mass of drug released
- straignt channel pore has tortosity of 1
- channel with mass of spherical beads unifmr size tortosity is 2-3
assumptions of the 2nd Higuchi equation
- pseudo-steady state is maintained during release
- A >Cs at all times (excess solute present)
- C=) at all times (perfect sink conditions)
- drug particles are much smaller than the matrix
- diffusion coefficient remains constant
- no interaction between drug and matrix
What is drug release controlled by in heterogenous metrix?
- solubility of pore forming materials
- resultant porosity of the matrix
- drug diffusion within the aqueous filled pores
-> release due to diffusion and dissolution
How to design controlled release systems
reservoir - coat tabs/granules in hydrophilic/hydrophobic polymer
matrix - composed of hydrophilic/hydrophobic polymer
What release profile do MR opioidanalgesics follow?
zero order release profile kinetic
advantages of MR opioid analgesics for mod/severe pain
- around the clock analgesia
- simpler dosing schedule
- more consistent and durable pain relief
- prevention fo abuse of opioids
oral formulation and drug is unstable in low pH (1-4)
formulated with enteric coating with carboxylic acid groups that are protonated and insoluble in low pH of stomach
dissolve in higher pH (7-9) of the intestines
Is degradability of polymer imortant for oral administration?
not required
Limitation of oral administration and how to overcome this?
the formulation’s time in the GIT (5-10hrs)
to over come this use elastic polymer that unfolds in the stomach and slowly degrades over days/weeks
What does SODAS stand for?
spherical oral drug absorption system
SODAS technology
- gelatin capsule that contains IR and ER brads of morphine
- ratio of 9:1 (w/w)
- reaches a therapeutic level of morphine within 30mins (IR beads) and maintains a plasmic conc for 24hrs (ER beads)
- sugar/starch core coated with morphine and fumaric acid (excipient)
- sustained release polymer coating -> Eudragit (not in IR beads)
- admin, gelatin cap dissolved, beads exposed to gastric fluid
- water enters the beads to dissolve the morphine and fumaric acid
- fumaric cid is an osmotic agent that brings water into the beads and controls pH -> release rate is independent to pH of GI fluid
- polymer coating is insoluble in GI fluid and controls morphine release rate by providing a diffusion barrier
SODAS technology pellets
- Kadian caps contain 1 type of pellet with IR and SR morphine
- coating formed from insoluble ethylcellulose layer with 2 polymers
- > PEG 6000
- > Eudragit
- cap admin, gelatin cap dissolved and released pellets into GI fluid
- acid stomach noly PEG 6000 dissolved forming small pores, IR morphine
- COOH groups on Eudragit protonated at low ph, insol in stomach
- pH inc in intestine, Eudragit dissolved and forms bigger pores
- drug diffused from pellets providing constant therapeutic conc of drug over 24hrs
formulation of Oromorph SR tabs
- morphine mixed with hydrophilic polmymer excipient
- > hydroxypropyl methylcellulose
- tab into GIT, fluid penetrates the tab allowing swelling of polymer and formation of viscous gel
- gel network controls rate of water diffusion into the matrix and also drug diffusion out of system
- 2nd drug delivery mechanism due to erosion of outer part of matrix
- therapeutic plasma conc maintained for 8-12hrs
OROS system
osmotic extended-release oral delivery system
-> push-pull technology
How does OROS technology work?
- drug reservoir composed of drug, PEG and polyvinypyrrollidone
- osmotic push layer consisting of PEG, NsCl and hydrocypropylcellulose
- coated by semipermeable shell membrane consisting of cellulose acetate and PEG
- in GIT, fluid flows through membrane at controlled rate, push layer expands and ejects suspended drug out of tablet through delivery orifice
- provided SR over 24hrs
- suitable for poorly water soluble drugs
drug used in OROS system
hydromorphone
advantages of transdermal administration
by-passes first pass hepatic metabolism
release over long period of tme improving patient compliance
drug used transdermally
fentanyl
Why can fentanyl be given transdermally compared to morphine?
- low Mr (286 Da)
- high lipophilicity (LogP = 717)
- optimal skin flux (1000x higher than morphine
fentanyl reservoir patch
- contains reservoir of fentanyl with dose for 3 days
- backing layer formed from polyester film that protects patch from environment
- liquid drug reservoir with dehydrated alcohol gelled with hydroxyethylcellulose
- membrane made with ethylene-vinyl acetate copolymer which controlls rate of release of fentanyl from reservoir
- silicone adhesive layer to adhere to patch to skin surface
problems with reservoir fentanyl patch
risk of drug leakage - accidental or intentional (cutting)
matrix transdermal patch
drug directly dissolved into a matrix composed of semi-solid formulation of polyacrylate adhesive
