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Dosage Forms Exam 3 Review > Dosage forms exam 3 review > Flashcards

Dosage forms exam 3 review Flashcards

1
Q

What are the wants for drug product performance?

A
  • ability of the drug to elicit a therapeutic response, to stay in a safe and efficacious window during the dosage regimen, and a lack of toxic or non-efficacious response. (described by pharmaco -kinetics and -dynamics)
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2
Q

What is the goal of Formulations?

A

develop new and promising therapeutic compound and have a reproducible effect. (content Uniformity)

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3
Q

Definition of Reproducible

A

refers to each dosage form containing between the same amount of drug (+/- 10%) and having the same performance in the body.

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4
Q

Blood Level vs. Time curve Important points

A
  • Cmax - the max blood/plasma concentration from a dosage form
  • Tmax- time to reach the max blood/plasma concentration
  • Absorption phase and disposition (can’t control)
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5
Q

Disposition

A

Distribution, Metabolism, Excretion (Elimination is M and E)

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6
Q

Relationship between absorption and disposition

A

As disposition begins to increase the absorption decreases.

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7
Q

What is the absorption rate defined by?

A

drug properties, excipient/drug composition, physiological barriers between GI tract and systemic circulation.

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8
Q

Blood Level vs Time curve (Area Under Curve)

A

The area under the curve at Cmax,Tmax allows insight to bioavailability.

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9
Q

What is Absorption rate controlled by?

A

formulation parameters that are optimized to provide a Cmax and Tmax associated with a safe and efficacious response in patients.

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10
Q

Druggability

A
  • look at binding as well as drug like properties that are favorable for product translation.
  • assess the ability of new chemical entities to bind to the drug target
  • in vivo models.
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11
Q

How to find targets for druggability

A
  • contrasting gene expression in healthy and afflicted patients can yield potential genes to target.
  • pharmacogenomic methods.
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12
Q

pharmaceutically tractable genome

A

genes that encode proteins which can be targeted by small molecular compounds for pharmaceutical use

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13
Q

Developability

A
  • refers to drug product performance (where it breaks down, where stable, where ionized)
  • ADME and solubility are important factors.
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14
Q

Relationship between druggability and developability

A

Target based on druggability and optimize based on developability (ADME)

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15
Q

What important factors are taken into account in terms of FORMULATION

A
  • Physicochemical properties of the API
  • physicochemical properties and composition of the formula.
  • Physiological barriers that influence bioavailability.
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16
Q

What are physicochemical properties of the drug that affect absorption?

A
  • solubility
  • stability in solution
  • lipophilicty
  • molecular size
  • pKa of ionizable groups
  • physical state of drug.
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17
Q

What is Partitioning?

A
  • partition coefficient: ratio of concentrations in 2 immiscible solvents (octanol and water)
  • octanol and water don’t accurately describe the intracellular conditions b/c membrane is not pure lipid and cytosol is not pure water.
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18
Q

pH-partition hypothesis

A
  • for drugs absorbed by a passive, transcellular mechanism; permeability transport depends on the fraction of unionized drug at intestinal pH
  • generally as Ko/w increases the solubility decreases.
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19
Q

How do you overcome effects of pH-partition hypothesis

A

Change the ionization/functionalize the compound (prodrug activity, salt selection)

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20
Q

What is Drug Performance

A

the ability of a drug to elicit a therapeutic response and to stay in a safe and efficacious range.

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21
Q

What formulation factors affect absorption?

A
  1. dosage form design (size, excipients, manufacturing)

2. Rate of drug release from dosage form (dissolution, coatings, osmotic pumps)

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22
Q

Define Excipients

A
  • usually inert substance that forms a vehicle for a drug

- added to therapeutically active compounds to improve appearance, bioavailability, stability, etc..

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23
Q

Are Excipients always inert?

A

NO! HIV drug example

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24
Q

Organoleptic senses AND why they are important

A
  • important in terms of clinical trials so what actual dosage form and placebo cannot be differentiated.
  • sight: size, shape, color, markings
  • smell: mask any unique odor
  • sound- tablet/pellet inside a capsule does not rattle
  • taste: mask any unique taste
  • touch
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25
Q

Effect of Compression force on a bed of powder.

A

too much: plastic

too little: elastic and falls apart.

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26
Q

Solid Dosage Form Requirements

A
  1. content uniformity
  2. good organoleptic properties.
  3. Stable shell life for 2 years.
  4. reproducible metrics for batches
  5. must not be friable
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27
Q

Physiological factors affecting Absorption

A

a. absorbing surface area
b. residence at time of absorption
c. pH changes in lumen
d. PERMEABILITY and perfusion
e. dietary fluctuations
complexation/protein binding
f. biliary uptake and clearance

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28
Q

Permeability

A

functional and molecular characteristics of transporters and metabolism

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29
Q

Epithelia (where it is found and types)

A
  • predominately on external surfaces (sit on a layer of extracellular matrix proteins)
  • polarized w/ directional transport
  • types: simple squamous, simple columnar, translational, stratified squamous
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30
Q

endothelial cells

A
  • type of epithelia
  • line the inside surfaces of body cavities, blood vessels, and lymph
  • have simple squamous morphology.
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31
Q

Tight Junctions

A
  • restrict movement between cells
  • allow for differing functions between the two membranes.
  • Polarized cells: apical (luminal facing); basolateral (albuminal-brain facing)
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32
Q

Effects of Cholesterol on Membranes

A
  • provide fluidity to membranes at lower levels
  • if too high- the membrane undergoes a phase transition and forms a liquid crystalline state (hardening atherosclerosis)
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33
Q

Intestinal transport mechanism (Passive)

A
  • non saturable

- paracellular and transcellular

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34
Q

Passive Paracellular movement

A
  • movement BETWEEN cells

- limited by molecular size, hydrophobicity, pKa of ionizable groups

35
Q

passive transcellular transport

A

-movement through cells.

36
Q

Carrier Mediated Transport

A
  • saturable
  • active transport (requires energy)
  • facilitated diffusion (energy independent)
37
Q

Be able to interpret Caco-2 vs PAMPA data

A
  • PAMPA (x axis) = pure lipid bilayer
  • Caco-2 (y axis)
  • midline/slope line = passive diffusion
  • above the line = absorptive influx and/or paracellular transport (faster)
  • below the line = slower than predicted; secretory and efflux transport, metabolism.
38
Q

Drug Transporters Roles

A
  • membrane bound proteins widely distributed throughout the body that have a role to move important molecules across membranes.
  • crucial determinant of tissue and cellular distribution of drugs.
39
Q

Absorption routes of Permeability

A
  • influx transporter, passive paracellular, passive transcellular, metabolism. efflux of metabolite
  • can be many routes of permeation that contribute to the net.
40
Q

Absorptive

A

transfers substrates into systemic blood circulation

41
Q

secretory

A

transfer substrates from the blood circulation into bile, urine, and/or GI lumen.

42
Q

GI tract epithelia

A
  • oral cavity: stratified squamous
  • esophagus: stratified squamous
  • trachea: pseudo stratified
  • stomach: columnar epithelia cells mixed w/ other types
  • small and large intestines: columnar mixed w/ other types
  • Rectum: upper= simple columnar; Lower moves from stratified squamous non-keratinized to stratified squamous keratinized.
43
Q

General role of the Stomach

A
  • digest food and control the flow of its contents into the intestine
  • processes food into fluid chyme for nutrient absorption
  • pH protects against most bacteria and allows pepsin to function (pH increases w/ food consumption)
44
Q

Organization of the Stomach

A

Fundus, Body, Antrum

45
Q

Fundus

A

contains gas and produces contractions to move stomach contents

46
Q

Body

A

reservoir for ingested food and fluids

47
Q

Antrum

A

lowest part of the stomach, funnel shaped, contains the pyloric region and controls flow into the small intestine.

48
Q

Phases of Gastric Emptying

A

1: food eaten; no activity 40-60 min
2: mixing contractions in stomach and small intestines (40-60 min)
3: stomach: powerful contractions empty stomach of digestible food. Intestine: distally migrating peristalsis
4: stomach empty of digestible and indigestible food; contractions diminish

** at any of the phases food can move into fed state until stomach empties.

49
Q

Time from mouth to anus

A

24-32 hours

50
Q

Where does most absorption occur?

A

SMALL INTESTINE

51
Q

Where does most colon drug absorption occur?

A

ascending region closest to the small intestine.

52
Q

Function of the Colon

A

fluid and electrolyte absorption

53
Q

why does most absorption occur in small intestine?

A
  • because of the large surface area

- have fold of Kerckring, villi, and micro villi (all these folds increase the SA and more absorption can occur)

54
Q

Columnar Epithelium (Intestines)

A
  • form a single layer of absorptive cells
  • Crypt region: 3 times more crypt than villi; undifferentiated cells that proliferate
  • Villus region: absorptive enterocytes
55
Q

How does relining of GI tract occur?

A

cells from the crypt region migrate to the villus tip and are sloughed off. (entire lining of GI tract is replaced every 2-4 days)

56
Q

Colon characteristics

A
  • transport is much slower than in small intestine
  • responsible for water and electrolyte reabsorption
  • leads to formation of solid fecal matter
57
Q

Purpose if ileocaecal valve

A

limits flow of food from the ileum into the caecum and vice versa

58
Q

3 layers of mucosa in colon

A
  1. muscularis mucosae
  2. lamina propria
  3. epithelium
59
Q

Length and Residence time throughout the GI tract

A

-stomach: get delivery and absorption (bottom may be most ideal bc pH doesn’t change-heavy drugs)

  • illeum: 2-3 hours of residence time
  • colon: 15-48 hours and lots of normal flora
60
Q

Residence time in GI tract with age

A
  • why fiber is so important
  • elderly patients become anal retentive
  • longer time in colonic transit (upwards of 100 hrs vs children around 40 hours)
  • b/c of this longer time and elderly patient can get more drug delivered potentially so important to monitor.
61
Q

Gastric Emptying affect on residence time

A
  • heavy meal can cause a delay in gastric emptying which leads to longer residence time.
62
Q

Rectum Epithelium

A
  • transitions as you go down from non-keratinized to keratinized.
  • highly folded
  • the non-keratinized allows for drug absorption
  • low residence time
63
Q

What are some sources of variability in drug responses between patients

A

-genetic factors, environmental factors, physiological factors

64
Q

Dissolution bath as a determinant of intestinal volume

A
  • dissolution baths 500-900 mL of water which is a lot more than actual body conditions (overestimates what is actually in small intestine)
  • idea that drug goes into a dissolution bath is not an accurate representation of the small intestine, but it works.
65
Q

Can there be variation in GI transit times within a single patient?

A

YES; gastric residence differs dramatically, gastric emptying controls colonic absorption where greater GI residence leads to higher absorption. (amount of food can influence)

66
Q

Where does bile get reabsorbed

A

in the jejunum

67
Q

drug solubility changes along the GI tract

A

-BUFFER CAPACITY: more resistant to change the better off it is. can affect the amount of drug that is ionized vs unionized.

68
Q

Why is the intestine broken down into many small sections?

A

-because there is variability between each of the sections that causes a drug to behave differently.
(variability in pH/bile distribution, permeability, blood flow distrib, transporter distrib.)

-want to target window where absorption is going to be optimized.

69
Q

Clinical Considerations

A
  • One size formulation do not fit all
  • so much variability in GI tract regions
  • diet and chemical exposure varies
  • pharmacogenetics (mutations)
  • gut microbiome
70
Q

Importance of the Plasma vs Time curve

A

-it can describe many processes –> including ADMET, bioequivalence, bioavailiabilty.

71
Q

Bioavailability

A

the rate and extent of drug absorption

72
Q

bioequivalent

A

does not mean that the therapeutic effect if 2 dosage forms are equivalent.

73
Q

DOSE

A
  • amount of chemical in which the whole organism is treated.
  • local concentration of the chemical at the biological response site.
74
Q

What is the relationship between dose and receptor concentration a function of?

A

ADME

75
Q

Relationship between dose and toxic effect

A

In between MEC and MTC = safe and efficacious
above MTC = toxic response
below MEC = not therapeutic response

76
Q

Coatings use

A

-applied to control dissusion rates and modify the release properties of the drug from the interior (applied to outside of dosage form)

77
Q

What can coatings do?

A

-protect against air, mask taste, provide special drug release.

78
Q

Enteric Coatings

A
  • added to dosage form to prevent the early release of an API in a region where it may undergo chemical or metabolic breakdown.
  • release in the small intestine to protect against gastric juices.
79
Q

Sustained Release

A

slow the release of API such that its appearance in the systemic circulation is delayed and/or prolongs and its plasma profile is sustained in duration

80
Q

controlled release

A

implies a reproducibility and predictability in the drug release kinetics. allows us to maintain narrow drug plasma conc. steady state.

81
Q

steady state

A

the rate going into the body must equal the disposition.

82
Q

Processes that are required for oral drug absorption of monolithic dosage forms

A

drug molecules at the surface dissolve to form a saturated solution; the dissolved drug can diffuse through solution to the absorbing mucosa. (solubility, dissolution, and permeability)

83
Q

Effect of particle size

A

surface area increased when solids are broken up into smaller pieces and the greater the SA leads to increased dissolution rates.

Dosage Forms Exam 3 Review (1 decks)

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