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Pharm304 > Lecture 7: oral drug delivery II > Flashcards

Lecture 7: oral drug delivery II Flashcards

1
Q

What are the two main classes of mechanism of drug absorption?

A

transcellular (across cells)

paracellular (between cells)

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2
Q

What does transcellular absorption encompass?

A

passive diffusion
active transport
facilitated diffusion
endocytosis

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3
Q

What is passive diffusion

A

simple diffusion

  • concentration gradient = driving force
  • no energy comsumption
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4
Q

What is active transport?

A

a form of carrier mediated diffusion where

  • energy is required as the driving force
  • can occur from low concentration to high concentration
  • peptide, nucleotide, sugar, bile acid, amino acid, organic ion, vitamin transporters
  • abundant in SI. each carrier system is concentrated in a specific segment of the SI
  • many peptide drugs e.g. penicillins, cephalosporins, ACE inhibitors or amino acid like drugs use this
  • can become saturated
  • may have competition for same transport system by similar substances
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5
Q

What is facilitated transport?

A

a form of carrier mediate transport

  • requires concentration gradient as driving force
  • faster rate
  • can be saturated and subject to inhibition
  • minor route for drug absorption
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6
Q

what is endocytosis?

A

primary mechanism to absorb macromolecules

  • used by fat soluble vitamins like A, D, E, K
  • used for vaccine absorption (polio)
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7
Q

What are the different types of endocytosis?

A

receptor mediated

non-receptor mediated

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8
Q

what are examples of non receptor mediated endocytosis?

A

pinocytosis, adsorptive endocytosis, phagocytosis

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9
Q

What is paracellular drug absorption?

A

usually via aqueous pores between cells

  • SI is relatively leaky
  • importance of paracellular drug absorption decreases down the GIT
  • used by ions, sugars, amino acids, peptides at concentrations above the capacity of their carriers
  • also the route for small hydrophilic and charged drugs
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10
Q

Why is efflux of drugs from the intestine significant?

A

This is where proteins expel specific drugs back into the GIT
-p-glycoprotein

significant as it reduces absorption, however some drugs are targeted to these efflux pumps

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11
Q

What are the main factors influencing oral bioavailability?

A

physichochemical factors
biopharmaceutics classification scheme
dosage form factors
patient factors

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12
Q

What are the physicochemical factors which affect oral bioavailability?

A

1) dissolution and solubility

2) drug absorption factors

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13
Q

What affects dissolution and solubility?

A

governed by the Noyes Whitney equation (rate = DA(Cs-C)h

  • physiological factors
  • drug/formulation factors
  • factors affecting concentration of drug in solution in GIT
  • poorly soluble drugs
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14
Q

What are examples of physiological factors?

A
  • presence of food
  • surfactant levels in gastric juice and bile salts
  • agitation
  • concentration of drug in GI fluids
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15
Q

What are examples of drug/formulation factors?

A
  • surface are and particle size
  • solubility in pH in the diffusion layer
  • pKa
  • salt form
  • crystal form (polymorphism, amorphous, solvates)
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16
Q

What are examples of factors affecting concentration of drug in solution in GIT?

A
  • complexation (e.g. streptomycin binds to mucin to reduce bioavailability)
  • micellar solubilisation
  • adsorption (e.g. charcoal reduces rate and extent of absorption)
  • chemical stability
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17
Q

What are the drug absorption factors?

A

drug dissociation
lipid solubility
molecular size and hydrogen bonding

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18
Q

what is the relevance of the pH partition hypothesis?

A

relates to drug dissociation and lipid solubility

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19
Q

What is the pH partition hypothesis?

A
  • the gut epithelial = lipid barrier for drugs which are absorbed by passive diffusion
  • only lipid soluble drugs pass through the barrier
  • most drugs are weak electrolytes so only their unionised form will pass through
  • the extent of ionisation of the drug depends on the pka of the drug and the pH of the environment

henderson hasselbach equation

pH = pKa + log (A-/HA)

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20
Q

WHat are the limitations of the pH partition hypothesis?

A

The extent of the unionised form is not the only factor determining rate and extent of absorption

  • weak acids still quite well absorbed from SI due to large surface area
  • some ionised drugs are readily absorbed
  • does not take into account of effect of mucosal unstirred layer
  • movement of water in and out of GIT also affects the rate of passage
21
Q

What is lipid solubility?

A
  • measured by partition coefficient
  • drugs with higher lipid solubility exhibit greater affinity for GI membrane and are better absorbed but if logP>3, it makes them more susceptible to metabolism and biliary secretion.
  • within a homologous serious drug absorption generally increases with lipophilicity
22
Q

What is the significance of molecular size and hydrogen bonding?

A
  • MW needs to be ideally <500Da for transcellular passive diffusion but larger examples exist also
  • too many H bonds is detrimental for absorption as the larger number of H bonds , the poorer the absorption.
23
Q

What is the biopharmaceutics classification scheme?

A
  • scientific framework for classifying ddrug substances based on aqueous solubility and intestinal permeability
  • guide to determine whether in vitro-in vivo correlation can be expected (brand bs. generics)
  • used as a practical starting point to consider issues related to absorption and suitable dissolution test conditions to use
24
Q

What are the main factors considered in the biopharmaceutics classification scheme?

A

solubility
permeability
dissolution

25
Q

What is the significance of solubility in the BCS?

A

a drug substance = highly soluble when the highest dose strength is soluble in 250mL or less of aqueous media at pH 1-7.5, 37 degrees C

relevant as aqueous solubility of <100ug/mL indicates drug is problematic in vivo

26
Q

What is the significance of permeablity in the BCS?

A

This is based on fraction of dose absorbed.

a drug substance = highly permeable when the extent of human absorption is 90% or more of an administered dose.

27
Q

What is the significance of dissolution in the BCS?

A

IR product considered rapidly dissolving when no less than 85% of labelled amount of drug dissolves within 30 minutes

28
Q

What is class I of the BCS?

A

high solubility/high permeability

  • ideal properties for absorption
  • not usually a problem to demonstrate bioequivalence of generic drugs
  • metoprolol, propranolol
29
Q

What is class II of the BCS?

A

low solubility/high permeability

  • common combination
  • in vivo dissolution rate = rate limiting step for absorption
  • demonstration of BE of diff. formulations or generics is important
  • NSAIDs, CV drugs, antifungals, carbamazapine, naproxen etc.
30
Q

What is class III of the BCS?

A

high solubility/low permeability

  • permeability is rate limiting
  • appropriate formulation is critical to maximise the time that high drug concentrations in contact with absorbing site
  • acyclovir, neomycin, atenolol, ranitidine
31
Q

What is class IV of the BCS?

A

low solubility/low permeability

  • inherent limitations to efficacy by oral delivery
  • furosemide
32
Q

What is an example of a drug that isboderline BCS classifications?

A

-chlorothiazide is borderline class III and IV
-a 100mg dose gives 60% bioavailability, soluble in 250mL
a 500mg dose gives a bioavailability of 20-30%, soluble in 1250mL

33
Q

What is the BCS definition of rapidly dissolving?

A

the drug must meet the criteria at these 3 pHs:

  • 0.1N HCl or stimulated gastric fluid USP without enzymes
  • pH 4.5 buffer
  • pH 6.8 buffer or stimulated intestinal fluid USP
34
Q

What is the BCS definition of permeation?

A

Where a drug demonstrates:

  • absolute bioavailability in humans
  • in vivo or in situ intestinal perfusion in animals
  • in vitro permeation - human or animal tissues using a chamber
  • in vitro permeation across a monolayer of cultured human cells (Caco-2 cells whih are adenocarcinoma colon cells)
35
Q

can a generic drug have a different colour, order or inactive ingredient to a brand drug?

A

yes as long as it has the same dosage, safety, strength, route of administration, quality, performance and intended use.

36
Q

Why is BE testing doing?

A

to relate a generic formulation to innovator formulation which is used to establish safety and efficacy

required for approval

37
Q

What is a waiver of in vivo bioavailability and bioequivalency studies?

A

document specifying that a BE test is not required.

38
Q

What drugs does the waiver apply to?

A

intermediate release solid oral dosage forms based on the BCS.

BCS class I 
BCS class II only in cases where in vitro in vivo relationships may be developed
39
Q

What drugs does the waiver NOT apply to?

A

BCS III and IV
drugs with narrow therapeutic range
products to be absorbed in the oral cavity e.g. buccal, sublingual

40
Q

what is dissolution rate a function of?

A

solubility, formulation

41
Q

What is disintegration rate a function of?

A

formulation

42
Q

what is solubilisation rate a function of?

A

solubility

43
Q

what is permeability rate a function of?

A

molecular structure, salt form, excipients

44
Q

What class of drug woud kd &kp = fast be?

A 
class I.
fast dissolution and permeablity rate
45
Q

What class of drug would kd»kp be?

A 
class III and IV
permeation is the rate limiting step
46
Q

what class of drug would kd«kp be?

A 
class II
where dissolution is the rate limiting step
47
Q

What are the advantages of the oral route?

A
  • patient acceptability and compliance
  • large surface area (~200m^2)
  • rich blood supply
  • prolonged retention
  • possibilities of controlled release
  • low cost of therapy
48
Q

What are the limitations of the oral route?

A
  • variability
  • adverse reactions
  • adverse environmental effects
  • high metabolic activity
  • extremes of pH
  • intestinal motility
  • mucus barrier
  • p glycoprotein efflux
  • impermeable epithelium

Pharm304 (21 decks)

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