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
