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828 Dosage > Oral Absorption > Flashcards

Oral Absorption Flashcards

1
Q

Required process for oral absorption of monolithic dosage forms

A
  1. Drug molecules at surface dissolve to form saturated solution
  2. Dissolved drug molecules diffuse from high to low concentration
  3. Drug moecules diffuse through bulk solution (GI fluids) to the absorbing mucosa and are absorbed
  4. Replenishment of drug molecules in diffusion layer achieved by further dissolution
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2
Q

Dissolution

A

Solid tablet -> gradient -> bulk solution (GI fluids)

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3
Q

Effect of particle size

A

-increased surface area leads to increased dissolution rate
-break into smaller pieces to increase surface area

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4
Q

Rate of dissolution

A

-(dM/dt)
-change in amount of mass that appears in solution over time

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5
Q

Rate of dissolution equation (Noyes-Whitney)

A

dM/dt = (DS/h) (Cd-Ca)

D=diffusion coefficient (Fick’s 1st)
S= surface area
h= thickness of stationary layer
Cd = concentration of drug in donor
Ca = concentration in bulk solution

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6
Q

Dissolution rate is proportional to

A

-rate of diffusion (D)
-surface area
-difference in concentration gradient

-increase in one will increase dissolution vice versa

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7
Q

Dissolution rate is inversely proportional to

A

-h
-increase h = less steep gradient
-take more time for molecule to move

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8
Q

increase stirring rate

A

-decreases h
-increases dissolution rate

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9
Q

Permeability vs dissolution

A

diffusion across a barrier instead of an unstirred layer

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10
Q

Partition coefficient

A

must be included in permeability to account for changes in environment between insise and outside membrane

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11
Q

Can remove Ca if we assume sink condition

A

concentration in membrane is negligible compared to GI fluids

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12
Q

Permeability equation

A

dM/dt = (DSKCd/h) = PSCd

dC/dt = PSCd/V

D=diffusivity
S=surface area of boundary
K= partition coefficient (solubility inside barrier/solubilty outside)
Cd = donor (GI) concentration
h= thickness of barrier (GI cell membrane
P= (DK)/h = permeability

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13
Q

Factors limiting oral drug absorption

A
  1. solubility (cant get enough drug in solution)
  2. Dissolution (cant get drug out of tablet)
  3. Permeability (cant get across Gi membrane)
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14
Q

Solubility limited

A

-characteristic of drug itself
-poorly soluble drugs limited as candidates
-small Cd value
-form dissolves fast and drug permeates readily
-increasing dose doesnt increase blood levels as GI fluids are already saturated

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15
Q

Dissolution Limited

A

-drug unable to dissolve into solution from dosage form in sub-saturated fluid
-takes longer than absorption in intestines
-due to poor formulation/manufacturing
-tablet needs to dissolve but survive shipping and handling

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16
Q

Permeability limited

A

-characteristic of drug itself
-dissolution fast with sub-saturated fluids
-increasing amount of drug (Cd) increases absorption (dM/dt)

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17
Q

Physiochemical constraints of solubility limited factors

A

-dissolution fast
-permeability fast

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18
Q

solubility limited observations

A

-gut saturated by high does
-absorption does NOT increase with increase dose

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19
Q

Physiochemical constraints of dissolution limited factors

A

-Tdiss greater than residence time in small instestine
-permeability fast

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20
Q

dissolution limited observations

A

-can be enhanced by particle size reduction
-absorption increases with increased dose

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21
Q

Physiochemical constraints of permeability limited factors

A

-permeability low regardless of solubility
-dissolution fast

22
Q

Permeability limited observations

A

Absorption increases with increased dose

23
Q

Biopharmaceutics classification system (BCS)

A

-predicated on known human absorption and dissolution data
-intended to be applies to drugs in clinical use
-does NOT incorporate transporters or metabolism
-NO pharmacogenetic considerations
-several agents can have more than one classification
-4 classes

24
Q

Class I

A

-high solubility and permeability

25
Q

Class II

A

-low solubility
-high permeability

26
Q

Class III

A

-high solubility
-low permeability

27
Q

Class IV

A

-low solubility and permeability

28
Q

Biopharmaceutics Drug Disposition Classification system (BDDCS)

A

-can predict from earlier stages
-incorporates transporters, enzymes, interplay
-drug disposition characteristics
-better for in vivo bioequivalence based biowaivers

29
Q

Class 1

A

-high solubility and metabolism

30
Q

Class 2

A

-low solubility
-high metabolism

31
Q

Class 3

A

-high solubility
-poor metabolism

32
Q

Class 4

A

-low solubility
-poor metabolism

33
Q

Effect of food absorption

A

-on gastric emptying time
-absorption of L-dopa inhibited by amino acids produced from breakdown of proteins
-calsium in diet inhibits absorption of tetracycline

34
Q

Effect of drug metabolism within GI tract on absorption

A

-enzymes
-within epithelial cells
-microflora

35
Q

Oral absorption

A

interplay of physiochem properties of drug, formulation, and physiological barriers

36
Q

Generic drug

A

-drug product comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality, performace, and intended use
-therapeutic equivalence

37
Q

therapeutic equivalence

A

-pharmaceutical equivalence
-bioequivalence
-same identity, strength, quality, safety, efficacy

38
Q

Pharmaceutical equivalents have the same

A

-active ingredient
-dosage form
-route of administration
-strength/concentration
-can differ in shape, excipients, color…

39
Q

Bioequivalence

A

-pharmaceutical equivalents whose rate and extnt of absorption are not statistically different when administered to humans at the same molar dose under similar experimental conditions

40
Q

Bioequivalence measurements

A

-in vivo measurement of active moieties in biological fluids
-in vivo pharmacodynamic comparison
-in vivo limited clinical comparison
-in vitro comparison

41
Q

same AUC

A

-does NOT equal bio/therapeutic equivalents
-Carbamazepine

42
Q

Carbamazepine (anticonvulsant/analgesic)

A

-treats seizures
-almost insoluble in water
-76% protein bound in blood
-hepatically metabolized via CYP3A4
-nonlinear kinetics
-28 diff approved preoral presentation and manufacturer combinations

43
Q

Study of 2885 pateints receiving phenytoin, carbamazepine, or valproic acid

A

-30% reported an issue with switch to generic product with same AUC

44
Q

Qualifications for bioequivalence

A

-90% confidence interval of the ratios of the test to reference log-transformed mean values for AUC and Cmax are within 80-125%
-differences in Cmax and Tmax were due to faster dissolution of genereic products comparative to the RLD

45
Q

IVIVC??

A

-all 4 products show linear relationship between %dissolved to %absorbed
-but NO correlation could be found to predict bioavailabilty of all 4
-no correlation possible between dissolution rate and AUC
-THESE PRODUCTS ARE NOT INTERCHANGABLE

46
Q

Mimicking clinical condition

A
  1. consideration of patient related variables
  2. patient variables not accurately assessed during development and scale up
  3. Absorption windoes are defined more on physical, chemical properties rather than physiology
  4. better in vitro and in vivo testing models needed to optimize dosafe dorm design and scale up
47
Q

Drug performance (PK/PD)

A

controlled by interplay of excipients (formularion), physiochemical properties, and physiological barriers between GI tract and site of action

48
Q

Oral formulations

A

can control absorption rate (Kabs) which has to be optimized with respect to disposition to yield a safe and efficacious response

49
Q

Dosage form design

A

-dynamic and unpredictable
-patient habits must be considered

50
Q

Generic formulations

A

-not the innovator
-can cause problems with performance

828 Dosage (27 decks)

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