Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Dosage Forms > Exam 3 Third Set of Lecture Slides > Flashcards

Exam 3 Third Set of Lecture Slides Flashcards

1
Q

What is the process for oral absorption of monolithic dosage forms?

A

drug molecules at the surface dissolve to form a saturated solution → dissolved drug molecules pass throughout the dissolving fluid (diffuse) from area of high to low concentration → drug molecules diffuse through the bulk solution to the absorbing mucosa and are absorbed → replenishment of drug molecules in the diffusion layer is achieved by further dissolution

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

How does surface area increase?

A

when solids are broken up into smaller pieces → for example from tablets to granules to particles

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Increased surface area leads to what?

A

increased dissolution rate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

How does h get smaller?

A

with more churning and turning you have

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is the rate of dissolution (dM/dt)?

A

The change in the amount of mass that appears in solution over time

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is the rate of dissolution dependent on?

A
  1. D = diffusion coefficient (Fick’s)
  2. S = surface area of tablet/granules (more SA, more dissolution and more can get in)
  3. h = thickness of stationary layer
  4. Cd = concentration of drug in the donor (x=0)
  5. Ca = concentration of drug in bulk solution (x=h)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Dissolution rate is proportional to what?

A

Diffusion rate (D) → increased rate of diffusion implies increased dissolution

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Dissolution rate is also proportional to what?

A

tablet/particle surface area → increased area for the drug to diffuse away

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is the third thing that dissolution rate is proportional to?

A

the difference in the concentration gradient → molecules want to go from high to low concentration

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is dissolution rate inversely proportional to?

A

thickness of stationary layer (h) → increased h means a less steep concentration gradient → having an equal dissolution rate will take more time for a molecule to move to bulk concentrations

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

How can you decrease h?

A

Increasing the stirring rate (aka agitating it) → increased stir rates leads to increased dissolution rate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is permeability?

A

A rate in the dissolution across a barrier (cell membrane) instead of an unstirred layer → have to include the partition coefficient (K) to account for the changes in the environment between the inside and outside of barrier → can remove Ca if sink conditions are assumed

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What are sink conditions?

A

if less than 10% of what we have in the donor is going across the membrane

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is the equation for permeability?

A

P = (DK)/h in which D is diffusivity, K is the partition coefficient and h is the thickness of the GI cell membrane

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the 3 factors that can limit the ability of a drug to absorb after oral administration?

A
  1. solubility → can’t get enough drug into solution
  2. dissolution → can’t get drug out of tablet
  3. permeability → can’t get drug across GI cell membrane
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What does it mean when a drug is solubility limited?

A

Drugs that have poor solubility are limited as druggable candidates, has a Cd value (no drug is coming out), dosage form can dissolve fast and permeate/crystalize

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What is the hallmark of solubility limited drugs?

A

Increasing the dose does not increase blood levels since GI fluids are already saturated

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What does it mean when a drug is dissolution limited?

A

Drug is unable to dissolve into the solution from the dosage form in sub-saturated fluid, dissolution time is greater than the time for absorption in the intestines → often due to poor formulation or manufacturing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What does it mean that a drug is permeability limited?

A

Similar to solubility limited, fast dissolution with sub-saturated fluids

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What is a hallmark of a drug that is permeability limited?

A

Increasing the amount of drug increases absorption → also increases Cd by increasing drug amount and dM/dt (absorption) also increases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

For permeability rate limited absorption, what is the rate limiting factor?

A

Absorption rate across the intestine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What is the difference between the permeability rate limited absorption graph compared to the dissolution rate limited absorption graph?

A

Permeability → drug in solution is much higher and solid drug decreases rapidly
Dissolution → drug in solution is much lower and solid drug decreases more evenly

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What are the physicochemical constraints of solubility limited?

A

Dissolution and permeability is fast → absorption does not increase with increased dose

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What are the physicochemical constraints of dissolution limited?

A

Tdiss is greater than residence time in the small intestine and permeability is fast → dissolution is enhanced by particle size reduction and absorption increase with increasing dose

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What are the physicochemical constraints of permeability limited?

A

Permeability is low regardless of solubility but dissolution is fast → amount of drug absorbed increases with increased dose

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What is Class I?

A

solubility and permeability is high → drug gets across perfectly → example is acetaminophen and NSAIDs (usually not subject to bioavailability problems)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What is Class II?

A

has low solubility → factor influences dissolution would also affect bioavailability → examples are cyclosporin and digoxin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

What is Class III?

A

has low permeability → tend to be absorbed in upper intestine → examples include furosemide and captopril

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

What is Class 4?

A

has low solubility and permeability → poor candidate for oral administration → example is vancomycin and neomycin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

What happens with classes II and III?

A

have to do bioavailability testing to show there is the same amount of absorption as the innovator product, might not have to test patients

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

What is the definition of a generic drug?

A

Drug product that is comparable to a brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

What is involved with therapeutic equivalence?

A

pharmaceutical equivalence and bioequivalence (aka AUC)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

When is a generic product judged to be therapeutically equivalent to the reference listed drug?

A

When it has the same identity, strength, quality, safety, and efficacy → not mandated for a lot of drugs

33
Q

What are pharmaceutical equivalents?

A

has the same AI, same dosage form, same route of administration, identical in strength or concentration and may differ in characteristics like shape, excipients, and color

34
Q

What is bioequivalence?

A

Pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to humans at the same dose under similar experimental conditions

35
Q

What are the in vivo measurements of active moieties in biologic fluids?

A
  1. in vivo pharmacodynamic comparison
  2. in vivo limited clinical comparison
  3. in vitro comparison
36
Q

What were the results of the questionnaire based study assessing switch to generic formulation of the same drug product (phenytoin, carbamazepine, valproic acid)?

A

about 70.5% reported no problems after the switch to the generic product but 30% of respondents reported an issue with a switch to a generic drug product (such as seizures reappearing) → differences in the Cmax and Tmax were due to faster dissolution of the generic products compared to the RLD → indicates a potential issue with repeated dosing

37
Q

What drug do some people believe that should be given a biowaver?

A

Carbamazepine since it is borderline class II

38
Q

A drug product is considered bioequivalent if…

A

the 90% confidence interval of the ratios of the test to reference log-transformed mean values for AUC and Cmax are within 80-125%

39
Q

What is IVIVC?

A

Take in vitro release rates in the dissolution bath and correlate them with the release/absorption rate seen in vivo

40
Q

Are generic drugs always interchangeable?

A

NO

41
Q

What really controls the dosage form?

A

patient response

42
Q

What are the 4 ways to mimic clinical conditions?

A
  1. dosage form design requires consideration of patient related variables
  2. patient related variables are not accurately assessed during development and scale up
  3. absorption windows are defined more on physical chemical properties and not physiology
  4. better in vitro and in vivo testing models are required for optimizing dosage form design and scale up
43
Q

What is drug performance (pharmacokinetics/pharmacodynamics) controlled by?

A

the interplay of excipients (formulation), the physicochemical properties of the drug, and the physiological barriers between the GI tract and the site of action

44
Q

Oral formulations control what?

A

absorption rate (Kabs) which is then optimized with respect to disposition to yield a safe and efficacious response

45
Q

What is the significance of dosage forms being dynamic and unpredictable?

A

patient habits have to be considered for dosing regimens

46
Q

Why can generic formulations cause some problems with performance?

A

generic formulations are not 100% the same as the innovator

47
Q

Why are children considered to be therapeutic orphans?

A

Developing medicines for children is not as developed since children don’t need chronic therapies since they don’t have chronic conditions or have cancer like adults

48
Q

How is the pharmacokinetics of drugs in pregnancy complex?

A

Physiological changes can alter ADME of drugs and toxicity is a significant concern since there is a fetus

49
Q

What can all impact the fetus?

A

genetics, diet, environment

50
Q

What has fetal imprinting been linked to?

A
  1. cardiovascular disease (Barker hypothesis)
  2. neurological disorders
  3. obesity/diabetes
51
Q

What is interesting about the placenta?

A

The placenta is a single layer of cells that controls and keeps the fetus in → comes from the sperm and the egg fusing so half of the placenta is male (which should be rejected by the body but doesn’t because of hormonal changes)

52
Q

During the Renaissance area, what were the typical environmental exposures?

A

infectious agents, fire byproducts (particulates, PAHs, CO), and heavy metals (lead, mercury)

53
Q

What are the typical environmental exposures today?

A

infectious agents, fire byproducts, heavy metals (palladium, cadium), industrial chemicals, chlorination byproducts, vehicular emissions, pesticides

54
Q

What are some pediatric pharmacology issues?

A
  1. utero malformations (ex. thalidomide)
  2. utero programming of cancer (ex. exposure to xenobiotics)
  3. animal models have different sensitivity to xenobiotic exposure than humans
  4. xenobiotic exposure can lead to changes in developmental PK/PD
55
Q

How can the placenta protect the fetus?

A

A malnourished mother can still provide 100% of nutrients to the fetus

56
Q

What were the 1962 Kefauver-Harris Drug Amendments?

A

They required efficacy and safety demonstration for FDA approval and marketing

57
Q

What are some legislative incentives/mandates in place to promote pediatric development?

A

FDA → Pediatric Plan, BPCA, PREA
EU → Pediatric Investigation Plan (PIP)
WHO → Make Medicines Child Size

58
Q

What are some challenges that have discouraged the testing of drugs on children that include the lack of:

A
  1. incentives for companies to study drugs in neonates, infants, and children
  2. technology to monitor patients and assay very small amounts of blood
  3. suitable pediatric clinical infrastructure for drug trials
59
Q

What percent of drugs have pediatric labeling?

A

20-30%

60
Q

How has the FDA encouraged pediatric studies?

A
  1. financial incentive to conduct studies
  2. increased studies resulted in new labeling of 40 drugs
  3. pediatric studies have been required for the approval of a selective number of new drugs
61
Q

What types of developmental changes are occurring from conception to adulthood?

A
  1. organ development
  2. drug transporter and metabolizing enzyme ontogeny
  3. pharmacodynamics and toxicokinetics
62
Q

Why is descriptive pharmacology in pediatric patients lacking?

A
  1. children are not mini adults (dosing based on scaling is not always predictable)
  2. animal studies are not predictable
  3. clinical studies with children have ethical and financial hurdles
  4. administration of the drug can also be problematic
63
Q

What has the Pediatric Biopharmaceutics Classification System (PBCS) been used for?

A

to expedite generic and drug repurposing formulations for industry

64
Q

What 3 factors is classification based on that influence the drug’s bioavailability from a peroral formulation?

A
  1. solubility
  2. intestinal permeation across the intestinal barrier
  3. dissolution rate
65
Q

What is the BCS classification?

A

Class I: rapid dissolution for immediate release
Class II: dissolution criteria are critically needed
BCS Class III: very rapid dissolution
BCS Class IV: same as class II

66
Q

What drives safety and efficacy?

A

Disposition → need to consider distribution, metabolism, and elimination in the system

67
Q

What happened with the methotrexate (MTX) study?

A

1883 patients were treated with high dose of MTX and the clearance differences were associated with single nucleotide polymorphism that altered the function of 1B1 that led to higher doses → low clearance rates were associated with higher toxicity so dose lowering adjustments and higher hydration rates are required in children with that phenotype

68
Q

How can the relevance of animal models limit extrapolation to humans?

A
  1. length of gestation and timing of events
  2. relative organ function maturity at birth
  3. species differences in some transport proteins and regulatory machinery
69
Q

What factors govern the regulation of transporter expression and activity during growth and development?

A
  1. nuclear receptor regulation

2. endocrine changes

70
Q

What are the 3 major challenges in studying pediatric drug transporters?

A
  1. limited availability of quality pediatric tissue for protein quantification and assessment of transporter function
  2. lack of transporter specific probes to assess in vivo function
  3. ethical and practical challenges with performing nontherapeutic studies in children
71
Q

What are some biological challenges with pediatrics?

A
  1. ontogenic changes

2. compositional changes

72
Q

What are some clinical challenges with pediatrics?

A
  1. clinical trials

2. caregiver requirements

73
Q

What are some formulation challenges with pediatrics?

A
  1. dosage form selection
  2. flexibility in dosing
  3. excipient selection
  4. taste masking
74
Q

What is the paradigm shift in industry?

A

Protect children FROM clinical research → protect children THROUGH clinical research

75
Q

What are the new challenges based on the paradigm shift?

A
  1. children are not mini adults
  2. pediatric patients need to be age classified
  3. pediatric patients need age appropriate formulations that are primarily made by compounding
76
Q

What is the Safety and Toxicology of Excipients for Pediatrics Database?

A
  1. is a collaboration between EMA and NICHD
  2. draws attention to use of traditional excipients like co-solvents
  3. encouraging greater use of solid dosage forms
77
Q

What is the importance of mini-tablet platform formulation?

A
  1. ability to incorporate BCS Class I and III
  2. easy translation to market formulation → pediatric compliance, flexible dosing, and protected from degradation of vehicle or stomach
  3. minimal excipients → single filler, disintegrant, lubricant with functional coatings
  4. same or similar manufacturing conditions → constant size
  5. fractional factorial DOE approach
78
Q

What are the advantages to pharmaceutical films?

A
  1. acceptable for patients with dysphagia (swallowing difficulties)
  2. ease and accuracy of dosing
  3. increased stability compared to solutions/suspensions
  4. faster onset of action
  5. life cycle management
79
Q

What are the disadvantages of pharmaceutical films?

A
  1. difficult to manufacture
  2. moisture sensitive
  3. limited dosing capacity
  4. increased packaging costs

Dosage Forms (5 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions