increasing the permeability Flashcards
why are the majority of immediate release drugs are in the oral form?
– Higher patient compliance than other routes
and other dosage forms.
– Simple and convenient administration.
– Fast and cost-effective manufacturing
compared to other dosage forms
what is the BCS
a mean of classifying drugs based
on their solubility and permeability.
what does the absorption need to happen?
– The drug must be in molecular form.
– The drug must have sufficient permeability to cross
the plasma membrane of epithelial cells.
When a rapid onset of action is required from a solid
dosage form:
↑ solubility & ↑ dissolution + ↑ permeability.
what are the BCS classes
class 1 high solubility and permeability
class 2 low solubility and high permeability
class 3 high solubility and low permeability
class 4 low solubility and permeability
what are the two factors that affect the BCS classes
- Solubility: the drug substance is considered highly
soluble if:
– The highest dose strength is soluble in < 250 ml
water over a pH range of 1 -7. - Permeability: the drug substance is considered highly
permeable if:
– The absorption in humans is > 90% of an
administered dose
remember
permeability is KD\h
rate of absorption = PAC
what does the passive absorption of the drug depends on
– The drug concentration (Cd)
– The area of absorptive tissue (A)
– The physicochemical properties of the drug (K
& D).
we can predict the bad drug absorption based on the rule of 5, what is the rule of 5?
poor absorption might happen if the drug have
- More than five hydrogen bond donor groups
- A molecular weight over five hundred (500
Daltons) - A partition coefficient over five (log P)
- A sum of nitrogen and oxygen atoms in the
molecule over ten (2 times five)
the rule of 5 is a prediction and drugs with active transport wont follow it
ok
what is class 1 (high , high)
– Most suitable for immediate release dosage forms
– The absorption rate is higher than elimination rate
– With the addition of appropriate excipients and suitable
formulation procedure delayed, sustained and
controlled dosage forms can be developed.
what is class 2 (bad solubility high permeability)
– Limited bioavailability due to poor solubility and/or poor
dissolution.
– Special formulation approaches are used to improve the
solubility or the dissolution rate of such drugs
what are class 3 and 4
– Very challenging
– Permeability of such drugs can not be
changed by formulation approaches
– If a high dose is required (high plasma
concentration) it is not possible to develop
these drugs.
– If high dose is required, the best option is to
optimize the chemical structure (and thus
physicochemical properties) to improve the
absorption a new chemical entity has to be
synthesized and developed.
give examples on some class 4 and 3 drugs
• Class IV
– HCTZ : maximum dose =100 mg/day and oral bioav =
~ 55% (variable, formulation and dose dependent)
– Taxol: Given IV, oral bioav = 6.5%
– Cyclosporine: maximum dose = 5 mg/kg/day
(psoriasis) and oral bioav = ~ 30% (10 – 60%)
• Class III
– Acyclovir : maximum dose = 800 mg x 5 daily and oral
bioav = ~ 10 -20%. (solubility = 2.5 mg/ml)
– Captopril: maximum dose =300 mg and oral bioav = ~
70 - 75%. (solubility = 160 mg/ml, short t0.5)
– Cimetidine: maximum dose = 800 mg and oral bioav
= ~ 60 - 70%. (the HCL salt is freely soluble in water,
short t0.5)
in the case of digoxin and griseovulvin
– Both drugs are BCS class II
– It is much easier to solve the solubility (and dissolution)
problem of digoxin compared to Griseofulvin.
– A complete intestinal absorption is expected when
digoxin is micronized, but it is not the case for
Griseofulvin
what is the law for the max dose absorbed in class 3 and 4
MAD= S.Ka.Vi.Ti
where:
– MAD: the maximum absorbable dose in mg
– S: solubility of the drug in mg/ml at pH 6.5
(average pH of the intestine, the major absorption
organ in the body)
– Ka
: intestinal absorption rate constant of the drug
per minute
– Vi: water volume in the small intestine (~ 250 ml)
– Ti: transit time of the dosage form in the small
intestine (~270 minutes)
what are the uses of the MAD equation
– Predicting solubility and permeability in vivo
where can the absorption happen in the git tract
• Absorption can occur in the: buccal cavity, stomach,
duodenum, jejunum, ileum, large intestine.
• The absorption takes place mainly in the small intestine
because of large surface area available for absorption in
this part of GIT.
– The surface area of jejunum and ileum (as a simple
tube) = 0.5 m2
– The real surface area of jejunum and ileum (due to
structure complexity) = 60 + 60 m2
(In some references it is estimated to be 200 m2
)
The surface area of other GIT parts:
– Duodenum: 0.1 m2
– Stomach: 0.1 m2
– Large intestine: 0.3 m2
why is the git so large?
The large surface area of small intestine can be
explained by its anatomy the presence of villi and
microvilli.
– Villi: lead to a relative surface area increase by a
factor of ~ 30
– Microvilli: lead to a further increase in the surface
area for absorption by a factor of ~ 600
what is the effect of the mucus layer
May decrease absorption of lipophilic drugs.
what is passive absorption
mechanism is by passive
diffusion. Can be divided into,
A. Transcellular: preferred by lipophilic drugs
B. Paracellular: preferred by hydrophilic drugs
(limited as pores and gaps between the
cells = ~0.1% of the total surface area of
the small intestine.
– Follows first order kinetics
what is active absorption
: occur by either
– Active transport
– Facilitated (carrier mediated) transport
– Examples: ACE inhibitors
– Active transport is saturable: follows Michaelis-
Menten kinetics.
what is Michaelis-Menten kinetics.
V= Vmax.Cd\Km-Cd
Where,
- V: the observed absorption rate
- Vmax: maximum absorption rate at drug saturation
- Km: the drug concentration when V = Vmax/2
-Cd: concentration of the drug
what are the barriers (factors that effects drug absorption negatively)
- Low solubility and slow dissolution
- Lipophilic nature of cell membrane limits the
absorption of hydrophilic drugs - The aqueous, stagnant mucus layer limits the
absorption of hydrophobic drugs - Variability in the gastric residence time
- Chemical and enzymatic degradation of the drug
(low pH and presence of digestive enzymes) - Metabolism
- Bacterial degradation
- P-glycoprotein drug efflux system
what is presystemic metabolism
– Luminal: caused by the large number of digestive
enzymes and other compounds evolved in drug
degradation. Example: peptidases, proteases, lipases
and esterases.
– First-pass intestinal metabolism: Occur by
• Brush border enzymes: phosphatases,
peptidases…etc. these enzymes have highest
activity in the jejunum, followed by the ileum.
• Metabolism in the enterocytes: include the
cytochrome P450 class, especially CYP3A4.
First-pass intestinal metabolism: occur during the absorption process.
First-pass hepatic metabolism: occur after absorption.
what is bacterial degradation
– The likelihood of enzymatic degradations of the drug
by enzymes of the bacterial flora increases as The number of microorganism (represented by
colony forming units) increases as we reach the
large intestine
– Bacterial enzymes include: reductases, esterases,
glycosidases, and sulfatases
A wide range of microorganisms are present in the to
aid digestion and support immune system.
what is the p-glycoprotein drug efflux system
PGPs are membranes proteins.
– Considered an effective efflux pump: transport
absorbed drug out of the epithelial cells of the small
intestine (enterocytes) back into the GIT.
– Usually co-localized with the enzyme CYP3A4
More efficient presystemic metabolism may be
achieved as the drug is repeatedly absorbed back
into the enterocytes and thus exposed for longer to
the degradation enzymes.
– PGP is present throughout the GIT but levels are
higher in the colon
how can we overcome the barriers
• Absorption can be enhanced by improving the
solubility and dissolution rate (class II drugs)
• For BCS class III and IV, absorption can be
improved by:
– Formulating prodrugs with enhanced lipophilicity
– Using absorption enhancers to disrupt the
epithelium barrier temporarily.
– Blocking drug metabolism or efflux
what is a prodrug
– The aim is to create lipophilic prodrugs that may more
easily overcome the absorption barriers of the GIT.
– Example: convert carboxylic groups or phosphate
groups to lipophilic esters
example: enalapril is much better than enalaprilat
what are absorption enhancers
they are molecules that
can be co-administered with the drug and that will
lead to a temporary disruption of the barrier
function of the epithelium.
– They can act by:
• Facilitating paracellular uptake: EDTA (A chelating agent that binds calcium and magnesium opening of tight junctions)
• Facilitating transcellular uptake: surfactants.
(– Ionic surfactants: sodium caprylate
– Nonionic surfactants: polyethoxylated castor oil
(cremophor EL) and polysorbate 80 (tween 80)
• Have toxic effects: can disrupt the barrier function
of the epithelium allow uptake of other
compounds with the drug.)
• Disruption of the aqueous stagnant boundary
layer
what are metabolism inhibitors
By co-administration of molecules that inhibit
presystemic metabolism or the PGP (P-Glycoprotein)
efflux mechanisms.
give examples on metabolism inhibitors
Example 1: the protease inhibitor drug saquinavir has
two formulations:
• Invirase (saquinavir mesylate): solid dosage form,
i.e., tablets and capsules.
• Fortovase (saquinavir): SEDDS in a soft gelatin
capsule
If it is to be used alone in the treatment of AIDS
Fortovase is preferred as it has higher bioavailability.
– However, Invirase may be used with ritonavir which is
an inhibitor of CYP3A4.
Co-administration of Invirase with ritonavir ↓
metabolism of saquinavir Invirase produce similar
bioavailability as Fortovase.
– Example 2: the co-administration of cyclosporine with
grapefruit juice.
• Grapefruit juice contains substances that
selectively inhibit intestinal CYP3A4 ↑
bioavailability of cyclosporine.
