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Dosage Forms II > Exam 3 Principles of Controlled Drug Delivery > Flashcards

Exam 3 Principles of Controlled Drug Delivery Flashcards

1
Q

What are some important tips regarding controlled drug delivery systems?

A
  1. can give a larger dose
  2. caution → if the device gets ruptured, too much drug may be released at once and the patient could overdose and die
  3. do not crush or chew ER tablets
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2
Q

What are the two different kinds of controlled drug delivery?

A
  1. temporal

2. spatial

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3
Q

What is temporal drug delivery?

A
  1. released over a period of time (can be over a week)

2. not delivered to a specific location

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4
Q

What are the two types of temporal drug delivery?

A
  1. sustained release → delayed and extended (over a period of time)
  2. pulsatile release → small amount of release at different times
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5
Q

What is an example of a temporal drug delivery system?

A

enteric coatings that can delay release until it gets to the intestine

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6
Q

What are characteristics of spatial drug delivery systems?

A
  1. systemic
  2. local → delivered to a specific location such as treating a local area of the skin (only small area of the skin)
  3. targeted → example is a cancer tumor and want the drug to be released at the site of the tumor
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7
Q

What are potential advantages of controlled drug delivery systems?

A
  1. maintain optimum drug concentrations → keeps the drug concentration from going up/down multiple times
  2. improve efficiency of treatment with less amount of drug
  3. minimize side effects → keeps drug concentration steady so not above or below the therapeutic window
  4. less frequent administration
  5. increase patient convenience and compliance with dosing regimen (adherence)
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8
Q

What are potential disadvantages of using a controlled drug delivery system?

A
  1. relatively high production costs → not as easy to make
  2. leakage of drug mass (dose dumping) → get larger amount of the dose than intended, example is a fentanyl patch
  3. difficult to stop drug release (especially if it is a tablet)
  4. biocompatibility of the delivery systems → can cause skin irritation at site so there is biocompatibility with the body that we have to consider
  5. necessity of surgical operation → in some cases
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9
Q

When is temporal control of drug delivery needed (or what is it needed for)?

A
  1. optimizing drug concentration time profiles at the site of action → maintains therapeutic window
  2. reducing administration frequency of the drugs → usually requires 1 administration
  3. stimulating multiple dosing via combination of an immediate release dosage and a pulsatile delivery system → requires bolus dose to get to immediate release and have maintenance dose that gives drug concentrations within the therapeutic window
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10
Q

When is temporal control of drug delivery not needed (for what types of drugs is it not needed for)?

A
  1. drugs with a long half life (like 6 days)
  2. drugs of which long term effect is undesirable
  3. drugs which require immediate effect → with extended release formulations, there is not that high of an immediate effect
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11
Q

What is the main benefit of a temporal control of drug delivery?

A

compared to giving multiple doses of a drug that have the potential for side effects (as it goes below and above the therapeutic window), a drug with temporal control will have drug concentrations that stay in the therapeutic window with minimizing side effects

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12
Q

What are the different drug release control mechanisms/systems?

A
  1. diffusion controlled systems → reservoir devices and matrix devices
  2. dissolution controlled systems
  3. erosion controlled systems
  4. osmotic systems → relatively pH independent
  5. swelling systems
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13
Q

What is the rate limiting step of diffusion controlled systems?

A

drug diffusion through the polymer network

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14
Q

What are two examples of diffusion controlled systems?

A
  1. reservoir systems → includes a drug reservoir that contains the bolus of drug and a release rate controlling membrane which needs to be intact
  2. matrix (monolithic) systems → includes a drug and matrix former
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15
Q

What is important to know about a reservoir system?

A

the release rate controlling membrane needs to be intact since the drug leaves the reservoir to go to the site of action but has to pass through the release rate controlling membrane → if the membrane becomes broke, the patient will get an immediate release of the drug which is BAD

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16
Q

What is important to know about matrix (monolithic) systems?

A

the drug diffuses from the polymer network → if it is far from the surface, the drug has to travel a farther distance but if it is close to the surface, the drug does not have to travel as far

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17
Q

What are examples of reservoir systems?

A
  1. Ocusert
  2. tetracycline periodontal fibers
  3. Norplant
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18
Q

How does Ocusert work?

A
  1. sits in the eye so that the drug can be ocularly delivered
  2. releases the drug at a constant rate into the eye since it is a reservoir system
  3. releases the drug on either side of the drug reservoir
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19
Q

What are the components of Ocusert?

A
  1. annular ring (is opaque white for visibility) → is a holder for the reservoir
  2. pilocarpine reservoir (aka drug)
  3. transparent rate controlling membranes that sandwiches the drug reservoir and annular ring → composed to ethylene vinyl acetate (EVA polymer)
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20
Q

How do the tetracycline periodontal fibers work?

A

is cylinder shaped and the drug release is associated to surface area of the cylinder → provides tetracycline 300 micrograms/cm

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21
Q

What are the components to the tetracycline periodontal fibers?

A
  1. the polymer membrane that is shaped like a cylinder (length of it is 1 cm and the thickness of the membrane is 25 micrometers) → composed of cellulose acetate
  2. the inner cylinder is the drug that is composed of tetracycline → the drug has a diameter of 200 micrometers within the cylinder
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22
Q

What are some important things to know about Norplant?

A
  1. is a non-erodible subdermal implant contraceptive → sends a constant release
  2. silicone capsules containing levonorgestrel
  3. trocar injections into the forearm → insert 6 capsules each that are 3 cm long and 24 mm outer diameter, 1.57 mm inner diameter and contain 36 mg of drug
  4. release rate of the drug is 70 ug/day total (3.8 ug/cm/day)
  5. plasma level of the drug is 0.3 ng/mL over 5 years
  6. was discontinued in the U.S. because of the disturbance of menstrual problems (caused irregular bleeding) and other factors such as pain, scar tissue, appearance, feel
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23
Q

What are some other good things to know about Norplant?

A
  1. bumps on the arm are visible from the six capsules
  2. need a relatively potent drug so small amount is needed → if the drug is not potent, need lots of the drug (not as ideal)
  3. need to make sure membrane is rigid and does not break
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24
Q

What is the equation for the drug release from diffusion reservoir?

A

M = DSKCst/h
(where M is the amount of drug flowing through a membrane, d is the diffusion coefficient, S is the cross section area (in cm^2), K is the partition coefficient of the membrane, Cs is the drug concentration in the reservoir, t is time, and h is the thickness of the membrane)

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25
Q

What is the partition coefficient K and how does it relate to drug release from a diffusion reservoir?

A

the partition coefficient refers to how the drug prefers to be in the membrane and then diffuses through the membrane to go to where it needs to go

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26
Q

What is one way to make drug release from the diffusion reservoir faster?

A

decrease the membrane thickness → membrane thickness is on the denominator so if that is smaller, the release rate will be faster

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27
Q

What is the drug release from a diffusion reservoir in terms of graphs?

A
  1. graph of M = kt → linear line (has a zero order release rate)
  2. graph of dM/dt = k → straight line (amount of drug is proportional to a constant over time
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28
Q

What does the pilocarpine release rate look like for Ocusert?

A

starts off really high to get an initial burst to get up to therapeutic level and then release rate decreases and remains constant over time

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29
Q

What are the four main layers of a nicotine patch?

A
  1. occlusive backing (clear) → covers nicotine and helps prevent nicotine evaporation → the very top layer of the patch
  2. drug reservoir → stores therapeutic nicotine which helps prevent the urge to smoke all day long
  3. rate controlling membrane → provides a steady stream of therapeutic nicotine to help prevent nicotine cravings
  4. adhesive and release liner → contains a loading bolus to provide patients with nicotine right from the start → the very bottom layer of the patch that attaches to the patient
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30
Q

What is important to know about matrix (monolithic) systems?

A
  1. does not have a zero order release rate → lots of the drug is initially released and less drug is released as time goes on
  2. drug and matrix former are not physically separated
  3. drug release depends on the device geometry → geometry dictates the release
  4. drug has to diffuse through the matrix so at the surface, drug release is fast whereas at the core, drug release is slow
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31
Q

What is an example of drug release from a diffusion matrix?

A

planner slab matrix diffusion device → drug close to the surface is released quickly so at the beginning the rate is fast and at the end, rate is slow

32
Q

What is the equation for the drug release rate of a diffusion matrix?

A

M = S[CsD(2C0-Cs)t]^(1/2)

where S is the area of the device, Cs is the drug’s solubility in the polymer, C0 is the total drug concentration (dispersed drug + dissolved drug), and D is the diffusion coefficient

33
Q

What is the simplified equation for drug release from diffusion matrix systems?

A

M = kt^1/2 aka the Higuchi equation (compared to the reservoir system that has the equation M = kt)

34
Q

What do the graphs of drug release from diffusion matrices look like?

A

graph of M = kt^1/2 → graph is hyperbolic and plateaus off so there is lots of drug released initially and slower release rate over time (not zero order)

graph of dM/dt = 1/2k(1/t^1/2) → graph is reverse of M = kt^1/2 graph where it is high initially and then decreases over time → good when there is a wide therapeutic window

35
Q

If the drug has a narrow therapeutic window, which type of diffusion controlled system is best for the drug?

A

reservoir system (but the membrane needs to remain intact) → matrix system is good when there is a wide therapeutic window

36
Q

What is an example of a matrix device system?

A

Habitrol patches (helps with nicotine cravings) → drug diffuses out of polymer and is released

37
Q

What are 4 examples of diffusion systems?

A
  1. membrane modulated → scopolamine → transderm-scop (Novartis) → has 4 layers that consists of backing membrane, drug reservoir, rate controlling microporous membrane, and adhesive
  2. membrane-modulated → nitroglycerin → transderm-nitro → has 4 layers that consists of backing membrane, drug reservoir, rate controlling microporous membrane, and adhesive
  3. adhesive dispersion → nitroglycerin → Deponit (Schwarz Pharma) → has 3 layers that consists of backing membrane, drug reservoir, and rate controlling adhesive
  4. matrix dispersion → nitroglycerin → Nitrodur (Schering) → has 2 layers that consists of backing membrane and drug + adhesive (=matrix) → use with wide therapeutic window!!!
38
Q

What is important to know about Nexplanon/Implanon NXT (Merck)?

A
  1. approved in the U.S. in 2006
  2. flexible rod (40 mm*2 mm)
  3. ethylene vinyl acetate copolymer (drug + matrix/coating)
  4. inserted just under the skin on the inside of the upper arm
  5. etonogestrel 68 mg (progestogen aka a synthetic hormone)
  6. lasts up to 3 years
39
Q

What are dissolution systems?

A

something has to dissolve first before the drug is released

40
Q

What are the two types of dissolution systems?

A
  1. encapsulated → contains drug that is encapsulated by a polymer membrane (the membrane has to dissolve first before the drug can be released)
  2. matrix → drug + polymer matrix where matrix will erode away then the drug can be released
41
Q

What is the equation for drug release via a dissolution matrix?

A

M = DSΔCt/h

where D is the diffusion coefficient, S is the surface area of the exposed solid, ΔC is Cs-C, and h is the thickness of the diffusion layer

42
Q

What is important to note about S in the rate of drug release from a dissolution matrix?

A

S is the surface area of the exposed solid Δ S changes with dissolution of the drug + polymer matrix

43
Q

The amount of drug released is equal to?

A

Hixson-Crowell cube root law → M0^1/3 - Mt^1/3 = kt

where M0 is the original mass, Mt is the mass at time t, and k is the cube root dissolution rate constant

44
Q

What does the graph for the drug release amount look like for the dissolution matrix system?

A

like the diffusion matrix graph where it increases rapidly and then plateaus over time

45
Q

How do osmotic systems work?

A

creates osmotic pressure by making water pass through the semi-permeable membrane to trap things

46
Q

What are characteristics of the film coating of osmotic systems?

A
  1. permeable for water
  2. not permeable for drug or excipients
  3. rigid → resist the hydrostatic pressure → pushes out the drug
47
Q

What is a one chamber osmotic system?

A

water flows in and the osmotic pressure forces material (aka drug) out of the orifice at a constant rate (drug will interact with the water)

48
Q

What is a two chamber osmotic system?

A

contains a flexible impermeable membrane that can move up as water diffuses in → the drug will not interact with the water while diffusing across the membrane

49
Q

Osmotic pressure is independent of what?

A

pH

50
Q

How is Concerta (methylphenidate) an example of an osmotic system?

A
  1. morning → the MPH overcoat provides immediate release of 22% of the dose within 1 hour (to get to the therapeutic window)
  2. 1 hour later → the push compartment expands, releasing MPH from MPH compartment 1 for the rest of the morning (slightly lower dose)
  3. afternoon → the push compartment continues to expand, releasing MPH from MPH compartment 2 during the afternoon

extended delivery results in efficacy through 12 hours → controlled release!

51
Q

How are one chamber and two chamber osmotic systems different?

A

one chamber system is much simpler where water comes in, drug comes out of the orifice compared to the two chambers system where there is a movable portion that separates drug from the water (good for unstable drugs)

52
Q

What is the equation for drug release from osmotic systems?

A

M = [(kS/h)Δpi*Cs]t

where k is membrane permeability to water, S is the area of membrane, h is the thickness of the membrane, Δpi is the osmotic pressure difference, and Cs is drug concentration

53
Q

How is the drug orifice made for osmotic systems?

A

by a laser drill

54
Q

What are components of an osmotic pump?

A

agent (aka drug), osmotic layer (has high osmotic pressure so water will come in to create pressure to force drug to come out), semipermeable membrane, impermeable reservoir, and flow modulator (limits how fast the drug is released and exerts back pressure)

55
Q

What is the equation used if the drug is additionally released from the device by simple diffusion through the membrane?

A

M = [(kS/h)Δpi*Cs]t + DSKCst/h

combines both the equation for osmotic systems and the equation for diffusion reservoir systems

56
Q

What is an advantage of osmotic systems?

A

the release rate of the drug is pH independent

57
Q

What do the graphs of drug release look like for osmotic systems?

A

graph of M vs t → linear line

graph of dM/dt vs t → straight line

58
Q

What are erosion controlled systems?

A

typically used for sustained release for a period of time → involves the erosion of the membrane or entire device itself where water breaks down polymer bonds and the drug is released → more drug is released when the matrix itself starts to break down

59
Q

What is the mechanism behind erosion controlled systems (PLGA microspheres)?

A

the initial release phase is controlled by diffusion of drug molecules that are on the surface or have access to the surface via pores in the microsphere matrix

the sustained release phase is determined by the erosion of the polymer → as the polymer erodes, entrapped drug molecules are released from the delivery matrix

60
Q

What are the two different types of erosion?

A
  1. surface erosion → taking off surface layers one by one where the device is dissolving (aka smaller and smaller area)
  2. bulk erosion → breaking part from within where there are lots of channels for molecules to diffuse out (area is remaining the same but drug molecules become more dispersed as drug molecules are released)
61
Q

What are some examples of erosion controlled systems?1.

A
  1. Zoladex → contains goserelin acetate with polymer matrix of PLGA used for prostate cancer, breast cancer, and endometriosis
  2. Lupron → contains leuprolide acetate with polymer matrix of PLGA or PLA used for advanced prostate cancer
  3. Nutropin → contains human growth hormone with polymer matrix of PLGA used for growth hormone deficiency
  4. Gliadel Wafer → contains BCNU (carmustine) with polymer matrix of polyanhydride used for high grade malignant glioma
  5. Sustol → contains granisetron (serotonin 3 receptor antagonist) with polymer matrix of tri(ethylene glycol) poly(orthoster) used for the prevention of acute and delayed nausea and vomiting
62
Q

What are Gliadel wafers?

A

contains BCNU/PCPP-SA (BCNU is carmustine) and is a biodegradable implant that contains drug inside and the implant can dissolve over time → wafers can be removed or be left in since it is biodegradable

63
Q

What are examples of polyanhydrides?

A

PCPP is a stable component but can be hydrolyzed or eroded

PCPP-SA contains sebasic acid (SA) that is more likely to be hydrolyzed

64
Q

What is the important of the ratio of SA in polyanhydrides?

A

polymer breakdown can vary due to how they’re put together and their monomers → a higher SA ratio (aka more SA) is more likely to be hydrolyzed so it degrades faster

65
Q

What is the ratio of SA in Gliadel wafers (BCNU/PCPP-SA)?

A

20:80

66
Q

What are some important things to know about Gliadel wafers?

A
  1. BCNU has a short half life (<15 min), has a dose limiting side effect (bone marrow suppression, pulmonary fibrosis), and systemic administration of BCNU is not desirable
  2. placed into the resection cavity of the tumor during the same operation when the cranium is still open
  3. no need to remove empty polymer remnants → because it’s biodegradable
  4. temporal control → BCNU is released in a time controlled manner → constant release
  5. spatial control → BCNU is released in the direct vicinity of the site of action → targeted delivery at site of tumor
67
Q

What are some things to know about the Lupron Depot?

A
  1. poly(lactic-co-glycolic acid) microspheres
  2. prostate cancer
  3. injected IM through 22G → 75 mg leuprolide acetate, 66.2 mg PLGA, 1.3 mg gelatin, 13.2 mg D-mannitol →→ roughly 50:50 mixture of drug and its excipients
  4. 1-4 month release for advanced prostate cancer → 7.5 mg/month
68
Q

What are some things to know about PLGA?

A

poly(lactic-co-glycolic acids) so contains glycolic acid and lactic acid that can be broken down by hydrolysis which can then be renally excreted or go to the TCA cycle to make CO2 and water → a relatively safe polymer to use!

69
Q

What are some other things to know about PLGA?

A

different PLGAs will have different viscosities, different lactide to glycolide ratios, and different degradation profiles

70
Q

Why is the Lupron Depot a sustained release formulation?

A

contains polylactic acid or PLGA that have longer release

71
Q

How does the Sustol extended release injection work?

A

incorporates granisetron into a unique polymer formulation and after a single SQ injection, the SUSTOL polymer undergoes hydrolysis, releasing granisetron in a controlled, sustained manner to prevent CINV for more than or equal to 5 days → after the granisetron has been released, the polymer disintegrates and is eliminated from the body

72
Q

What is the main thinking behind a depot injection?

A

injected into site by giving someone a shot → polymer dissolves over time which makes it a “depot”

73
Q

What is the polymer matrix used for Sustol?

A

tri(ethylene glycol) poly(orthoester)

74
Q

How is the formulation of Sustol made?

A

mix the drug and the polymer → drug molecules are encased within the polymer matrix → polymer dissolution → drug dispersion (aka polymer dissolves to release the drug)

75
Q

What are swelling controlled systems?

A

polymer swelling →

  1. the length of the diffusion pathways increases → decreasing drug concentration gradients → decreasing drug release rates
  2. the mesh size of polymer network increases → increasing drug diffusivities in the polymer network → increasing drug release rate
  3. tightly packed to less tightly packed → faster rate
76
Q

What are other drug delivery systems?

A
  1. drug is covalently bound to an insoluble matrix former (polymer) via hydrolyzable bondings → rate of hydrolysis + rate of diffusion of water and drug through the polymer network
  2. pulsatile release
  3. microchip based drug release

Dosage Forms II (20 decks)

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