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Biopharmaceutics > GI tract > Flashcards

GI tract Flashcards

1
Q

benefits of using oral drug delivery

A

non invasive, painless, cost effective manufacturing, improved compliance (patient more likely to follow drug scheme)

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2
Q

problem with using oral delivery

A

most drug molecules dont have the physiochemical properties to be orally bioavailable/ insufficient amount of drug available at site of action

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3
Q

describe the biopharmaceutics classification system

A

class i- high permeability high solubility
class ii- high p low s
class iii- low p high s
class iv- low p low s

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4
Q

oral dosage form approach for a class ii drug in BCS (high p low s)

A

increase surface area like reduce particle size/solid dispersion, use solvents or surfactants

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5
Q

oral dosage form approach for a class iii drug in BCS (low p high s)

A

use permeability enhancers, maximise local lumenal concentration

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6
Q

factors that affect absorption

A

pKA of drug, local pH

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7
Q

what is the main cellular barrier to drug absorption from GI tract

A

gastrointestinal membrane that separates lumen of stomach and intestines from systemic circulation

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8
Q

what does GI tract stand for

A

gastrointestinal tract

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9
Q

what 2 assumptions does the pH partition hypothesis suggest

A
  1. GI tract acts as lipid barrier towards weak electrolyte drugs which are absorbed by passive diffusion
  2. GI/blood barrier is impermeable to ionised (poorly lipid soluble) forms of drugs, only lipid soluble unionised species will pass across
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10
Q

3 principal factors that determine drug uptake

A

-dissociation constant (pKa)
-pH at absorption site (affects ionisation state)
-lipid solubility of drug (based on polarity of drug)

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11
Q

what is the absorption of a weak electrolyte drug determined by

A

the extent of ionisation of drug at absorption site

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12
Q

what equation to use to calculate extent of ionisation of a drug in a particular environment

A

henderson-hasselbach of a weak acid and % ionised

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13
Q

what is ion trapping

A

in stomach acetyl salicylic acid is unionised, in blood it acetyl salicylic acid is ionised, equilibrium strongly in favour of uptake into blood

-once it enters blood it’s in a different pH environment and in its ionised form so it wont diffuse back into stomach

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14
Q

problem with pH partition hypothesis

A

only gives qualitative description and not quantitative, cant predict drug uptake, eg. can only rank a series of similar drugs in order of uptake in a limited pH range

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15
Q

why are there deviations from expected results from the pH partition hypothesis in experiments

A

-microclimate pH
-available surface area
-presence of unstirred water layer
-absorption of ionised forms of drug

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16
Q

how does the absorption of ionised forms of a drug cause deviations from the pH partition hypothesis

A

GI tract is partially impermeable to ionised drug, ionised form is absorbed through intestines at a lower rate than unionised

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17
Q

how does the presence of an unstirred water layer cause deviations from the pH partition hypothesis

A

extra barrier to drug absorption, aqueous boundary layer, drug absorption separated into 3 main steps (lumen to mucosal unstirred layer to epithelial cell)

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18
Q

how is an unstirred layer of water created

A

incomplete mixing of luminal contents near the intestinal mucosal surface

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19
Q

effects of having an unstirred layer of water

A

drug absorption separated into 3 main rate processes

  1. diffusion from lumen to mucosal unstirred layer (MUL)
  2. diffusion through MUL
  3. absorption through membrane to cell

if 2<3 then 2 will be rate limiting step

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20
Q

why is drug movement by diffusion slow in the mucosal unstirred layer

A

the layer is static (not moving), unionised can diffuse across lipid membrane easily but struggle to get through MUL, diffusion varies with molecular weight, larger/more hydrophobic will be more affected, rate limiting barrier for intestinal absorption of lipids

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21
Q

what is microclimate pH

A

difference between pH at cell membrane and bulk lumen pH

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22
Q

microclimate and lumenal pH equation to explain absorption anomalies

A

MpH= A+B(LpH-7)+C(LpH-7)^3

MpH=microclimate pH
LpH= lumenal pH

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23
Q

limitations of using the unifying hypothesis

A

only applies to pure drug in controlled conditions absorbed by only diffusion

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24
Q

other factors to consider in unifying hypothesis

A

other uptake mechanisms, carrier mediated transport, fat uptake pathway, ion pairing, drug stability/formulation, patient factors

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25
Q

importance of dissolution

A

only substances in molecularly dispersed forms are transported across intestinal wall and absorbed into systemic circulation

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26
Q

noyes whitney equation

A

dm/dt= DA(Cs-C)/h

dissolution rate, diffusion coefficient (higher D= lower viscosity), surface area (larger SA=faster rate
), saturation solubility in diffusion layer, conc of drug in solution (lower conc=more fluid=higher dissolution rate), thickness of diffusion layer (thicker=slower)

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27
Q

what is solubility and dissolution rate

A

solubility= capacity of solute to dissolve in a solvent

dissolution rate= rate which solute dissolves

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28
Q

total solubility equation

A

Cs=[HA]+[A-]

(sum of solubilities of unionised and ionised form of the drug)

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29
Q

for weak acid what is the dissolution rate proportional to

A

1/[H+]

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30
Q

for weak base what is the dissolution rate proportional to

A

[H+]

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31
Q

what do weak acids dissolve best in

A

alkaline medium

32
Q

what do weak acids absorb best in

A

acid medium

33
Q

what do weak bases dissolve best in

A

acid medium

34
Q

what do weak base absorb best in

A

alkaline medium

35
Q

what happens if you increase surface area of contact with GI fluids

A

dissolution rate increases

36
Q

what does particle size reduction result in

A

increased dissolution rate if absorption of drug is dissolution rate limited

37
Q

what and how does a solid dispersion prevent aggregation

A

-drug formulated with another small carrier drug that is readily soluble

-soluble component dissolves leaving a microcrystalline drug

38
Q

what can microionisation of a hydrophobic drug lead to and its effects

A

aggregation, which leads to reduction in effective SA of drug exposed and leading to reduced dissolution rate and bioavailability

39
Q

what can aggregation lead to

A

reduced effective surface area/dissolution rate/bioavailability, leads to changes in compaction characteristics and tablet may not break apart

40
Q

what happens if drugs that are unstable in gastric fluid are exposed to more acid

A

leads to breakdown of drug and reduced bioavailabiltiy

41
Q

3 ways to achieve reductions in effective particle size

A
  1. solid dispersions- microcrystalline drug dispersed in carrier
  2. solid solutions- drug in molecular form dispersed in carrier
  3. use of wetting agents
42
Q

how can solid dispersions reduce particle size

A

drug is formulated with another small carrier drug, soluble component dissolves and leaves microcrystalline drug in better conditions

43
Q

how can solid solutions reduce particle size

A

molecule of hydrophobic drug dispersed in hydrophilic polymer, as carrier dissolves the drug is left in molecular form

44
Q

how can wetting agents reduce particle size

A

useful for hydrophobic drugs, surface of drug needs to wet easily to enable interactions to allow surface to dissolve, wetting agents help dissolution and improve bioavailabiltiy

45
Q

other ways to enhance dissolution rates

A

salt form, polymorphism, amorphous form, solvates

46
Q

precipitated drug will redissolve if

A

dissolve drug is absorbed, stomach fluid volume increases, contents of stomach enter intestine

47
Q

how can weak acid drugs be formulated into its salt form

A

formulate as sodium salt, when drug dissolves sodium ions are present in diffusion layer, pH raised in diffusion layer, more alkaline conditions are more favourable for drug, easier dissolve and better absorption

48
Q

most common salt forms of acidic drugs

A

sodium salts

49
Q

most common salt forms of basic drugs

A

chloride salts

50
Q

what is polymorphism

A

different crystalline forms of a drug

51
Q

what is crystalline

A

materials where its molecules are packed in a defined order that repeats

52
Q

what is amorphous form

A

no defined shape, no long range packing order

53
Q

benefits of amorphous form compared to crystalline and a disadvantage of amorphous

A

amorphous- more soluble, rapidly dissolving
crystalline- less soluble, slower dissolving, unabsorbed and therapeutically ineffective

but amorphous slowly converts to more stable crystalline over time so must stabilise drug in dosage form

54
Q

what are solvates

A

drug crystalises trapping molecules of the solvent within the lattice, if its water=hydrate

55
Q

what is the absorption of drugs dependent on

A

availability of drug, bulk solubility, dissolution rate, degree of ionisation

56
Q

what is absorption potential equation

A

Log(PfSV)/D

P=octanol water partition coefficient
f= fraction of nonionised drug at 6.5 pH
S=intrinsic solubility
V=volume of lumenal contents
D=dose

57
Q

what does the number of absorption potential imply

A

negative AP= poor absorption
>1.0= nearly complete absorption

58
Q

limitations of absorption potential

A

doesnt account for degradation in lumen/ non passive uptake mechanisms (eg. active transport)/ first pass metabolism/ paracellular routes, only indicates for absorption with no limitations of dosage formulation factors

59
Q

maximum absorbable dose equation

A

MAD= VSKata

V=intestinal dissolution volume
S=intrinsic solubiltiy
Ka=first order permeability constant
ta=GIT absorption transit time

60
Q

what is maximum absorbable dose

A

mathematical model to predict the max amount of drug that can be absorbed in a 6 hour time frame

61
Q

why 6 hour time frame in max absorbable dose equation

A

stimulate small intestinal residence time

62
Q

2 ways to avoid issues with acid/enzymatic hydrolysis leading to poor bioavailability and

A

prodrug administration, enteric coating

63
Q

what is prodrug administration

A

pharmacologically inert chemical derivatives that can be converted in vivo to active drug molecule to exert a therapeutic effect

64
Q

what problems can prodrug administration help with

A

chemical instability, low lipophilicity, poor aqueous solubility, poor distribution across membranes, rapid absorption when long term effect is required

65
Q

what are enteric coatings

A

pH sensitive polymers that is insoluble in acid but dissolve in neutral/slightly alkaline environment of the gut

66
Q

when are enteric coatings used

A

when drug is inactivated/destroyed in acid from stomach, drug is irritating to gastric mucosa, when bypass of stomach enhances drug absorption

67
Q

what is the dissolution rate of enteric coating affected by

A

pKa of polymer, pH of medium, ionic strength of medium

68
Q

if the molecular weight of enteric coating polymer is low what happens

A

polymer will dissolve and drug released rapidly

69
Q

if the molecular weight of enteric coating polymer is high what happens

A

polymer will swell into a gel layer that controls drug release

70
Q

limitations of solutions

A

acidic drugs as salt forms can precipitate in stomach, poorly water soluble acidic drugs may have better bioavailability as a well formulated suspension of free acid, hard to formulate

71
Q

types of delivery systems

A

solutions, soft/hard capsules, coated/uncoated tablets, excipients, complexation, adsorbtoion

72
Q

types of capsules

A

soft elastic gelatin and hard gelatin

73
Q

write about soft elastic gelatin capsules

A

filled with any liquid, slower rate than solution due to capsule breaking down and dispersion, better bioavailability than tablet, uptake by fat absorption pathway when delivering oils/emulsions

74
Q

write about hard gelatin capsules

A

disintegration of shell, contents should empty before all gelatin has dissolved, better than loosely packed tablets, no high compression forces, smaller particle=greater rate of absorption, use dilutent to minimise aggregation and maximise surface area

75
Q
A

Biopharmaceutics (11 decks)

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