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controlled drug release (MR opioids) Flashcards

1
Q

drug delivery systems that have no control of drug release

A 
tablets
capsules
solutions
suppositories
inhalers
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2
Q

What is a sustained release formulation?

A

formulations that should prolong biological activity

slow release of drug over a time period

may or may not be controlled release

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3
Q

What is a controlled release formulation?

A

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

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4
Q

2 types of systems that give control to drug release

A

sustained release

controlled release

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5
Q

graph for zero order release (controlled release)

A

straight line through origin

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6
Q

drugs that benefit from zero order/controlled release

A

anti-inflammatories
24hr release
eg. naproxen

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7
Q

advantages of controlled release dosage forms

A
  • reduced frequency of dosage
  • more effective utilisation of the therapeutic agent
  • lower incidence of side effects
  • improved control of disease state
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8
Q

problems/dangers with conventional products (not controlled release)

A

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)
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9
Q

coltrolled release time curve

A
  • one repeat action dosage form containing 2 doses
  • 1st is IR to reach the therapeutic window
  • 2nd is a maintenance dose
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10
Q

disadvantages of controlled release dosage forms

A
  • 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
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11
Q

principles for obtaining controlled/extended release preparations

A

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)
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12
Q

3 types of diffusion controlled drug delivery systems

A

reservoir
matrix
miscellaneous

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13
Q

RESERVOIR diffusion controlled systems

A

diffusion controlled by

  • a membrane (transdermal systems)
    • > made from polymers
  • OR a coating (tablets, patriculates, granules)
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14
Q

MATRIX diffusion controlled systems

A

homogenous systems (monolithic)

heterogenous systems (granular)

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15
Q

MISCELLANEOUS diffusion controlled systems

A

osmotically controlled systems

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16
Q

example of reservoir system

A

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
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16
Q

desscribe diffusion controlled release RESERVOIR system

A

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

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17
Q

3 types of formulations of reservoir systems

A

implantable
oral
transdermal

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18
Q

formula for the drug delivery rate

A

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

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19
Q

What parameter to decrease in the formula to extend the release?

A

decrease the thickness of the coat

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20
Q

describe MATRIX diffusion controlled delivery

A
  • 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
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21
Q

what is total conc of drug Co greater than (matrix system)

A

total conc of drug Co (dissolved and dispersed is greater then than the solubility of the drug in the matrix Cs

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22
Q

What does the Higuci equation depend on?

A

the rate of drug release was dependent on drug diffusion and not on the rate of drug dissolution

23
Q

What is A in the Higuchu equation?

A

total concentration dissolved and undissolved drug in the matrix

24
What is Cs in the Higuchi equation?
solubility or saturation concentration of drug in the matrix
25
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
26
Higuchi equation
dQ/dt = sq/ (ADCs/2t)
27
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)
28
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
29
What type of matrix is a granule?
porous/heterogenous | not homogenous
30
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
31
Higuchi equation for heterogenous matrix drug delivery
Q = sq/ (De/tor) (2A - eCs) (Cst)
32
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
33
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
34
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
35
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
36
How to design controlled release systems
reservoir - coat tabs/granules in hydrophilic/hydrophobic polymer matrix - composed of hydrophilic/hydrophobic polymer
37
What release profile do MR opioidanalgesics follow?
zero order release profile kinetic
38
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
39
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
40
Is degradability of polymer imortant for oral administration?
not required
41
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
42
What does SODAS stand for?
spherical oral drug absorption system
43
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
44
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
45
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
46
OROS system
osmotic extended-release oral delivery system -> push-pull technology
47
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
48
drug used in OROS system
hydromorphone
49
advantages of transdermal administration
by-passes first pass hepatic metabolism release over long period of tme improving patient compliance
50
drug used transdermally
fentanyl
51
Why can fentanyl be given transdermally compared to morphine?
- low Mr (286 Da) - high lipophilicity (LogP = 717) - optimal skin flux (1000x higher than morphine
52
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
53
problems with reservoir fentanyl patch
risk of drug leakage - accidental or intentional (cutting)
54
matrix transdermal patch
drug directly dissolved into a matrix composed of semi-solid formulation of polyacrylate adhesive

PHA333 (27 decks)

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