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PHARM 125 - Pharmaceutics > Modified Release > Flashcards

Modified Release Flashcards

1
Q

How does conventional/immediate release oral dosage form effect absorption and duration of action?

A

Drug is rapidly released and absorbed in the GI track, peaking plasma concentrations very quickly for a short duration of action

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2
Q

Define extended release (ER).

A

Releases drug slowly over a long time and maintains drug plasma level at a therapeutic level

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3
Q

Define delayed release (DR)

A

Delays release for a period of time to target a specific site in the body

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4
Q

What is the goal of modified release oral dosage forms?

A

To improve therapeutic profile of the drug and minimize side effects

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5
Q

What are other names are there for extended release according to USP?

A

Controlled release → release drug at a constant rate

Prolonged release → onset is delayed and drug is provided for absorption over a longer period of time

Sustained release → initial release of drug provides therapeutic effect followed by gradual release of the drug

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6
Q

What are some of the advantages of the modified release dosage form? (7)

A
  • reduced dosing frequency and accumulation of drug in the body
  • better patient acceptance and compliance
  • less fluctuation at plasma drug levels
  • reduced GI side effects
  • improved efficacy/safety ratio
  • usage of less total drug
  • may reduce cost of treatment for chronic diseases
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7
Q

What are some of the disadvantages of the modified release dosage form? (5)

A
  • dose dumping
  • tablets that remain intact may become lodged at some site in the GI tract
  • need of additional patient education
  • variable physiological factors (pH differences, GI motility)
  • removal of drug from system is difficult if not impossible
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8
Q

What are the physiochemical factors that must be taken into consideration when designing MRSDF? (6)

A
  1. Dose size
  2. Drug stability in the GI tract
  3. API solubility
  4. Partition coefficient
  5. API half-life
  6. Polymer structure
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9
Q

MRSDF design considerations: dose size

A

Large doses (>500mg) are hard to make into ER products because it requires 2 or more times the amount of drug as IR

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10
Q

MRSDF design considerations: drug stability in the GI tract

A

In MR, drugs stay in the GI tract for longer → more prone to acid-base hydrolysis and enzymatic biotransformation

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11
Q

MRSDF design considerations: API solubility

A

LOW (<0.1mg/mL) → not suitable to diffuse through a membrane

HIGH → rapid dissolution, difficult to decrease the rate to modify absorption

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12
Q

MRSDF design considerations: partition coefficient

A

Log K 1-3 = ideal for ER drug candidates

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13
Q

MRSDF design considerations: API half life

A

should be 2-8h

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14
Q

MRSDF design considerations: polymer structure

A

Effects the diffusion coefficient and release rate of a drug

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15
Q

What are the biopharmaceutical factors to be taken into consideration when designing MRSDF? (3)

A
  1. Anatomical factors of GI
  2. Dietary factors
  3. Physiological factors
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16
Q

MRSDF design considerations: anatomical factors of GI tract

A
  • absorption window is the specific region of the GI tract where absorption takes place
    • most absorptive region is the small intestine → short transit time ~3h
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17
Q

MRSDF design considerations: dietary factors

A

food intake will influence drug release rate, absorption rate and amount absorbed

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18
Q

MRSDF design considerations: physiological factors

A

metabolic enzymes and efflux mechanisms

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19
Q

What does grapefruit juice inhibit?

A

P-glycoprotein efflux and intestinal metabolism, enhancing bioavailability with some drugs

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20
Q

When is dose dumping very problematic?

A

Highly potent drugs with narrow therapeutic indexes

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21
Q

Drug release rate should balance rate of ______ to rate of _____

A

Balance rate of absorption to rate of elimination

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22
Q

What is required to balance rate of absorption and rate of elimination?

A

Drug release must be independent of amount of drug left in the dosage form and is constant over time (zero order kinetics)

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23
Q

What kinetics do most ER systems show?

A

FIRST ORDER → release is dependent on the amount of drug remaining in the dosage form over time

24
Q

What does reaction rate describe?

A

The change in concentration of a drug as a function of time

Describes the increase or decrease in the concentration of A within a time interval dt

Rate = +/- d[A]/dt

25
Q

What are the units of reaction rate?

A

Concentration versus time; mol/(L s)

26
Q

What are the types of modified release systems? (5)

A
  • diffusion controlled → reservoir and matrix devices
  • osmotically controlled systems
  • ion-exchange resins
  • gastric retentive systems
  • pH-sensitive delivery systems (delayed release)
27
Q

How is a reservoir diffusion system made?

A

Drug is in a core/reservoir surrounded by an inert water insoluble polymeric membrane (non-porous or with porous-forming polymers)

→ can be monolithic(1 unit or layer) or multi-particulate (granules)

28
Q

What is the rate controlling mechanism in a reservoir diffusion system?

A

drug partitioning into membrane with release into surrunding fluid by diffusion; rate of release is governed by Fick’s law for non-porous type

29
Q

What are some of the advantages of multiparticulates in the reservoir diffusion system?

A
  • minimized risk of dose dumping
  • more consistent in vivo performance
  • tailored release kinetics (depending on how many IR and ER pellets there are)
30
Q

What are the components of the core in a reservoir system?

A
  • active drug
  • filler
  • lubricant/glidant
31
Q

What are the components of the coating in a reservoir system?

A
  • membrane polymer (HPC, ethyl cellulose, polyvinyl acetate)
  • pore former (PEG)
  • plasticizer
  • colour/opacifier
32
Q

What is different in a reservoir system for low and high dose strength API?

A

HIGH → drug containing core, functional coat on top

LOW → placebo core with drug layer around it, functional coat on top

33
Q

What are the two preparation methods for reservoir diffusion systems?

A
  1. Coated granules or pellets by: extrusion-spheronization, rotary granulation, fluidized-bed coating, hot-melt coating
  2. Encapsulate in hard capsule or compress into tablets (multiple-unit pellet system/MUPS)
34
Q

What is a matrix diffusion system?

A

Made of drug dispersed homogenously throughout an inert, insoluble, swellable, or erodible polymer (matrix)

→ ONLY monolithic

35
Q

What is the rate controlling step for matrix diffusion systems?

A

Diffusion of drug out of the matrix

36
Q

Do matrix diffusion systems have a membrane?

A

NO

37
Q

What are some formulation factors that can affect the rate of release in a matrix system?

A
  • amount of drug in the matrix
  • porosity of the release unit
  • length of the pores in the release unit
  • solubility of the drug
38
Q

What are the three types of matrix diffusion systems

A
  1. Hydrophilic matrix systems/swellable soluble matrices
  2. Erosion controlled
  3. Inert polymer
39
Q

What are the properties of hydrophilic/swellable matrix systems?

A
  • drug is mixed with hydrophilic gel-forming polymer
    • HPMC
    • methylcellulose
    • acrylic copolymers
  • drug release controlled by diffusion of drug out of the gel layer
  • zero or fist order release
  • cost effective
40
Q

What are the properties of erosion-controlled matrix systems?

A
  • drug release rate is controlled by erosion of the matrix
  • first order release
  • can also be called hydrophilic matrix systems
  • bio-erodable matrices:
    • co-polymers of lactic and glycolic acid
    • lipids
    • waxes
41
Q

What are the properties of inert polymer matrix systems?

A
  • first order release, porous matrix
  • hydrophobic matricies:
    • ethylcellulose
    • carnauba wax
    • can include PEG → pore forming
42
Q

How do osmotically controlled systems work?

A

Uses osmotic pressure as the driving force to generate a constant release of a drug → water diffuses in and increases osmotic pressure forcing drug out through a laser drill hole

43
Q

What is the order of release for osmotically controlled systems?

A

ZERO → constant release over time

***membrane is permeable to water but not to the drug so it must come out through the pores

44
Q

What are the two types of osmotically controlled systems?

A
  1. Elemental osmotic pump (EOP): single-layer tablet
  2. Push-pull osmotic pump (PPOP): bilayer tablet
45
Q

What is the semi-permeable membrane of osmotically controlled pumps most commonly made of?

A

cellulose acetate and PEG

46
Q

What is an ion-exchange resin system?

A

Insoluble copolymers matrix containing ionizable groups capable of exchanging ions → reversible process

Resin and drug are prepared in beads or pellets

47
Q

What types of resins are there for IER?

A
  1. Strong cation IERs; sulphonic acid functional groups
  2. Weak cation IERs; carboxylic acid functional groups
  3. Strong anion IERs; trimethyl ammonium chloride
  4. Weak anion IERs; ammonium chloride or primary amine
48
Q

How does IER work?

A
  1. Loading of basic drug onto cation exchange resin
  2. Release of drug from resinate
49
Q

What are gastric retentive systems used for?

A

Retention of DF in the stomach for drugs that:

  • have narrow absorption window
  • act locally in the stomach
  • unstable in the colon
  • low solubility at high pH
50
Q

What are the advantages of gastric retentive systems?

A
  • reduce variability of drug release
  • local delivery and action
  • enhanced bioavailability
51
Q

What are the four types of gastric retentive systems?

A
  1. Floating delivery systems
  2. Muco-adhesive system
  3. Expandable system
  4. High density system
52
Q

How do pH controlled systems work and what are some examples of polymers used in these systems?

A

Change in pH results in a swelling or de-swelling of polymer → hydroxypropylmethylcellulose phthalate and polymethylmethacrylate (eudragit)

53
Q

What is the application of pH-controlled systems?

A

Colonic delivery systems: local delivery for the treatment of inflammatory diseases, infections, diarrhea and systemic delivery

54
Q

What is the process of release for pH-controlled systems?

A
  1. Acid insoluble cap and coating dissolves in intestinal fluids
  2. hydrogel plug expands in intestinal fluids
  3. hydrogel plug is ejected
  4. drug is released in colon

***this mechanism is hard to make and there are very few of these systems available

55
Q

What are the USP requirements for these types of dosage forms?

A
  1. Drug release → individual monographs have specific criteria for compliance with the test and test procedures
  2. In vitro-In vivo correlations (IVIVC) → process for developing this model is as follows:
    1. develop formulations with different release rates
    2. obtain in vitro dissolution and in vivo plasma concentration profile
    3. estimate the in vivo absorption or dissolution time course for each formulation
56
Q

What are the differences in methylphenidate release forms?

A

Concerta → osmotic pressure

Biphentin → capsule containing multi-layered beads

Ritalin → film coated, extended release tablets

PHARM 125 - Pharmaceutics (5 decks)

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