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)
2
Q
What is the goal of Formulations?
A
develop new and promising therapeutic compound and have a reproducible effect. (content Uniformity)
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.
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)
5
Q
Disposition
A
Distribution, Metabolism, Excretion (Elimination is M and E)
6
Q
Relationship between absorption and disposition
A
As disposition begins to increase the absorption decreases.
7
Q
What is the absorption rate defined by?
A
drug properties, excipient/drug composition, physiological barriers between GI tract and systemic circulation.
8
Q
Blood Level vs Time curve (Area Under Curve)
A
The area under the curve at Cmax,Tmax allows insight to bioavailability.
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.
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.
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.
12
Q
pharmaceutically tractable genome
A
genes that encode proteins which can be targeted by small molecular compounds for pharmaceutical use
13
Q
Developability
A
- refers to drug product performance (where it breaks down, where stable, where ionized)
- ADME and solubility are important factors.
14
Q
Relationship between druggability and developability
A
Target based on druggability and optimize based on developability (ADME)
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.
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.
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.
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.
19
Q
How do you overcome effects of pH-partition hypothesis
A
Change the ionization/functionalize the compound (prodrug activity, salt selection)
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.
21
Q
What formulation factors affect absorption?
A
- dosage form design (size, excipients, manufacturing)
2. Rate of drug release from dosage form (dissolution, coatings, osmotic pumps)
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..
23
Q
Are Excipients always inert?
A
NO! HIV drug example
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
25
Effect of Compression force on a bed of powder.
too much: plastic
| too little: elastic and falls apart.
26
Solid Dosage Form Requirements
1. content uniformity
2. good organoleptic properties.
3. Stable shell life for 2 years.
4. reproducible metrics for batches
5. must not be friable
27
Physiological factors affecting Absorption
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
28
Permeability
functional and molecular characteristics of transporters and metabolism
29
Epithelia (where it is found and types)
- predominately on external surfaces (sit on a layer of extracellular matrix proteins)
- polarized w/ directional transport
- types: simple squamous, simple columnar, translational, stratified squamous
30
endothelial cells
- type of epithelia
- line the inside surfaces of body cavities, blood vessels, and lymph
- have simple squamous morphology.
31
Tight Junctions
- restrict movement between cells
- allow for differing functions between the two membranes.
- Polarized cells: apical (luminal facing); basolateral (albuminal-brain facing)
32
Effects of Cholesterol on Membranes
- provide fluidity to membranes at lower levels
- if too high- the membrane undergoes a phase transition and forms a liquid crystalline state (hardening atherosclerosis)
33
Intestinal transport mechanism (Passive)
- non saturable
| - paracellular and transcellular
34
Passive Paracellular movement
- movement BETWEEN cells
| - limited by molecular size, hydrophobicity, pKa of ionizable groups
35
passive transcellular transport
-movement through cells.
36
Carrier Mediated Transport
- saturable
- active transport (requires energy)
- facilitated diffusion (energy independent)
37
Be able to interpret Caco-2 vs PAMPA data
- 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
Drug Transporters Roles
- 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
Absorption routes of Permeability
- influx transporter, passive paracellular, passive transcellular, metabolism. efflux of metabolite
- can be many routes of permeation that contribute to the net.
40
Absorptive
transfers substrates into systemic blood circulation
41
secretory
transfer substrates from the blood circulation into bile, urine, and/or GI lumen.
42
GI tract epithelia
- 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
General role of the Stomach
- 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
Organization of the Stomach
Fundus, Body, Antrum
45
Fundus
contains gas and produces contractions to move stomach contents
46
Body
reservoir for ingested food and fluids
47
Antrum
lowest part of the stomach, funnel shaped, contains the pyloric region and controls flow into the small intestine.
48
Phases of Gastric Emptying
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
Time from mouth to anus
24-32 hours
50
Where does most absorption occur?
SMALL INTESTINE
51
Where does most colon drug absorption occur?
ascending region closest to the small intestine.
52
Function of the Colon
fluid and electrolyte absorption
53
why does most absorption occur in small intestine?
- 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
Columnar Epithelium (Intestines)
- form a single layer of absorptive cells
- Crypt region: 3 times more crypt than villi; undifferentiated cells that proliferate
- Villus region: absorptive enterocytes
55
How does relining of GI tract occur?
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
Colon characteristics
- transport is much slower than in small intestine
- responsible for water and electrolyte reabsorption
- leads to formation of solid fecal matter
57
Purpose if ileocaecal valve
limits flow of food from the ileum into the caecum and vice versa
58
3 layers of mucosa in colon
1. muscularis mucosae
2. lamina propria
3. epithelium
59
Length and Residence time throughout the GI tract
-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
Residence time in GI tract with age
- 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
Gastric Emptying affect on residence time
- heavy meal can cause a delay in gastric emptying which leads to longer residence time.
62
Rectum Epithelium
- transitions as you go down from non-keratinized to keratinized.
- highly folded
- the non-keratinized allows for drug absorption
- low residence time
63
What are some sources of variability in drug responses between patients
-genetic factors, environmental factors, physiological factors
64
Dissolution bath as a determinant of intestinal volume
- 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
Can there be variation in GI transit times within a single patient?
YES; gastric residence differs dramatically, gastric emptying controls colonic absorption where greater GI residence leads to higher absorption. (amount of food can influence)
66
Where does bile get reabsorbed
in the jejunum
67
drug solubility changes along the GI tract
-BUFFER CAPACITY: more resistant to change the better off it is. can affect the amount of drug that is ionized vs unionized.
68
Why is the intestine broken down into many small sections?
-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
Clinical Considerations
- One size formulation do not fit all
- so much variability in GI tract regions
- diet and chemical exposure varies
- pharmacogenetics (mutations)
- gut microbiome
70
Importance of the Plasma vs Time curve
-it can describe many processes --> including ADMET, bioequivalence, bioavailiabilty.
71
Bioavailability
the rate and extent of drug absorption
72
bioequivalent
does not mean that the therapeutic effect if 2 dosage forms are equivalent.
73
DOSE
- amount of chemical in which the whole organism is treated.
- local concentration of the chemical at the biological response site.
74
What is the relationship between dose and receptor concentration a function of?
ADME
75
Relationship between dose and toxic effect
In between MEC and MTC = safe and efficacious
above MTC = toxic response
below MEC = not therapeutic response
76
Coatings use
-applied to control dissusion rates and modify the release properties of the drug from the interior (applied to outside of dosage form)
77
What can coatings do?
-protect against air, mask taste, provide special drug release.
78
Enteric Coatings
- 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
Sustained Release
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
controlled release
implies a reproducibility and predictability in the drug release kinetics. allows us to maintain narrow drug plasma conc. steady state.
81
steady state
the rate going into the body must equal the disposition.
82
Processes that are required for oral drug absorption of monolithic dosage forms
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
Effect of particle size
surface area increased when solids are broken up into smaller pieces and the greater the SA leads to increased dissolution rates.
