2. CONTENT
Definition
Purpose of bio availability
Factors affecting bio availability
Measurements of bio availability
Reasons for poor availability
Approches to enhance the bio availability
Methods of enhancement of bio availability
Reference
3. BIO AVAILABILITYBIO AVAILABILITY
BIO AVAILABILITY means the rate and
extent of drug reaches the systemic
circulation in its unchanged form
following the administration of a dosage
form
4. PURPOSE OF BIOAVAILABILITYPURPOSE OF BIOAVAILABILITY
For marketing approval of new drug, FDA meets
bioavailability studies
Establish the pharmacokinetic characters and it
is useful in establish dosage regimens
Bio availability studies are useful in determining
the safety, efficacy, identity, strength, quality
and purity of the drug product
6. A)Pharmaceutic factors :
1) Physicochemical properties of
drug
Drug solubility & dissolution rate.
Particle size & effective surface area.
Polymorphism & Amorphism.
Amorphous > metastable > stable
Pseudopolymorphism (Hydrates / Solvates )
Anhydrates > hydrates e.g. Theophylline,
Ampicillin
Organic solvates > non solvates e.g.
fludrocortisone
7. Salt form of the drug.
Weakly acidic drugs – strong basic salt
e.g.barbiturates , sulfonamides.
Weakly basic drugs – strong acid salt
Lipophilicity of the drug .
pKa of the drug & pH .
Drug stability.
8. 2) Dosage form characteristics &
Pharmaceutic Ingredients
Disintegration time (tab/cap)
Dissolution time.
Manufacturing variables.
Pharmaceutic ingredients( excipients /
adjuvants )
Nature & type of dosage form.
Solutions> Emulsions> Suspensions> Cap> Tab>
Enteric Coated Tab > Sustained Release
Product age & storage conditions.
9. B)Patient related factors
Age
Gastric emptying time .
Intestinal transit time .
Gastrointestinal pH .(HCL > Acetic > citric )
Disease States .
Blood flow through the gastrointestinal tract .
Gastrointestinal contents :
Other drugs .
10. Food .
Fluids
Other normal g.i. contents
Presystemic metabolism (First – Pass effect )
by :
Luminal enzymes .
Gut wall enzymes .
Bacterial enzymes .
Hepatic enzymes .
12. Route Bioavailability (%) characterstics
Intravenous 100 (by definition) Most rapid onset
(IV)
Intramuscular 75 to ≤ 100 Large volumes often feasible;
(IM) may be painful
Subcutaneous 75 to ≤ 100 Smaller volumes than IM;
may be painful
(SC)
Oral (PO) 5 to < 100 Most convenient; first pass effects
may be significant
Rectal (PR) 30 to < 100 Less first-pass effects than oral
Inhalation 5 to < 100 Often very rapid onset
Transdermal 80 to ≤ 100 Usually very slow absorption;
used lack of first-pass effects;
prolonged duration of action
13. MEASUREMENT OF BIO AVAILABILITYMEASUREMENT OF BIO AVAILABILITY
Divided in to three categories.
Pharmacokinetic method
Pharmacodynamic method
scientgraphy study
Selection of method depends on the:
Purpose of the study
Analytical method of drug
measurement
Nature of the drug product
15. PLASMA LEVEL-TIME STUDIESPLASMA LEVEL-TIME STUDIES
PRINCIPLE:
It is based on the assumption that
two dosage forms that exhibit super
imposable plasma level time profile
in a group of subjects should result in
identical therapeutic activity
16. FOR SINGLE DOSE STUDYFOR SINGLE DOSE STUDY
It requires collection of serial blood
samples for a period of 2 to 3 biological
half lives, after drug administration
And then analysis for drug concentration
By making a plot of concentration vs
corresponding time of sample collection
to obtain plasma level time profile
17. FOR MULTIPLE DOSEFOR MULTIPLE DOSE
Method involves drug administration
for at least 5 biological half lives
A blood sample should be taken at
the end of previous dosing interval
and 8 to 10 samples after the
administration of next dose
18. PARAMETERSPARAMETERS
3 parameters of these method used to
estimate the bio availability are:
Cmax : Peak plasma concentration.
Tmax : Peak time
AUC : Area under the plasma level-
time curve
22. CUT & WEIGH AND PLANIMETERCUT & WEIGH AND PLANIMETER
METHODSMETHODS
CUT & WEIGH: Plasma concentration profile are
plotted on smooth paper, these can be cut out
and weighed and the weight of the papers is
directly proportional to AUC
PLANIMETER : A planimeter is a percision
instrument which allows the calculation
of areas by tracing there outlines
23. TRPEZOIDAL METHODTRPEZOIDAL METHOD
It involves the breaking up of the
plasma con vs time profile in to several
trapezoids calculating the area of each
trapezoid and add them to obtain the
AUC
AUC = [(co+c1)(t1-
to)/2]+……… + (cn-1+cn)(tn-tn-1)/2
25. EXTENT OF BIOAVAILABILITYEXTENT OF BIOAVAILABILITY
FOR SINGLE DOSE STUDYFOR SINGLE DOSE STUDY
F=[AUC]oralDiv/ [AUC]ivDoral
Fr=[AUC]testDstd/[AUC]stdDtest
D = DOSE
ADMINISTERED
26. EXTENT OF BIOAVAILABILITYEXTENT OF BIOAVAILABILITY
FOR MULTIPLE DOSE STUDYFOR MULTIPLE DOSE STUDY
Fr=[AUC]testDstdTtest/[AUC]stdDtestTstd
T=Dosing interval
Bioavailability can also be measured by peak
plasma concentration at steady state,
Fr=[Cssmax]testDstdTtest/[Cssmax]stdDtestTstd
T=dosing interval
27. URINARY EXTRECTION STUDIESURINARY EXTRECTION STUDIES
PRINCIPLE: It involves urinary excretion of
unchanged drug is directly proportional toplasma
concentration of drug
Eg : thiazide diuretics, sulphonamides
For drugs that have urine as site of
action
eg: urinary antiseptics : nitrofurantoin.
28. METHOD FOR URINARY EXCRETIONMETHOD FOR URINARY EXCRETION
STUDIESSTUDIES
It involves collection of urine at regular intervals
for a time span equal to 7 biological half lives
Then analysis for unchanged drug in the
collected sample
Then determined the amount of drug excreted
in each interval and cumulative amount
excreted
29. PARAMETERS
(dxu/dt)max: Max urinary excretion rate.
(Tu)max: Time for Max excretion rate.
(Xu):Cumulative amount of drug
excreted in the urine
32. EXTENT OF BIOAVAILABILITY
FOR MULTIPLE DOSE STUDY AT
STEADY STATE
Fr=(Xu,ss)testDstdTtest/(Xu,ss)stdDtestTstd
(Xu,ss) It is the amount of drug excreted
in unchanged form during a single
dosing interval at Steadystate
33. ADVATAGES OF URINARY EXCRETION
STUDIES
These method is useful when there is a lack of
sufficiently sensitive analytic tech to measure
concentration of drugs in plasma with accuracy
Convenince of collecting urine samples.
Direct measurement of absolute and relative
bioavailablity is possible without the neccesity of
fitting the data to a mathematic model
When coupled with plasma level-time data,it can be
used to estimate renal clearance of un changed
drug,by
CLR=total amount of drug excreted unchanged / AUC
35. ACUTE PHARMACOLOGICAL
RESPONSE Acute pharmacological effect such as
change in ECG OR EEG readings,pupil
diameter etc is related to the time
course of a given drug
Bioavailability can be determined:
By construction of pharmacologic effect -
time curve
By dose-response graphs
36. THERAPEUTIC RESPONSE
This method is based on observing the
clinical response to a drug formulation
given to a patient suffering from disease
for which it is intended to be used
Draw back is difficult assessment of
relative bio availability between two
dosage forms of the same drug
37. SCIENTGRAPHY STUDY
Radioactive substances is used
to investigate the extent of
absorption of drugs, which are
directly introduced to the colon
or targeted to colon
38. REASONS FOR POOR
BIO-AVAILABILITY
Poor aqueous solubility or slow
dissolution rate.
Poor stability of the dissolved drug at the
physiologic PH
Inadequate partition coefficient and thus
poor permeation through the bio
membrane.
Extensive pre-systemic metabolism.
39. APPROACHES TO ENHANCE THE
BIOAVAILABILITY
THE PHARMACEUTIC APPROACH
THE PHARMACOKINETIC
APPROACH
THE BIOLOGIC APPROACH
40. METHODS FOR ENHANCEMENT OF
BIOAVAILABILITY
MICRONIZATION: Steroidal drugs, sulfa drugs,
griseofulvin
USE OF SURFACTANTS: Polysorbates increases
the bio avaialability of spiranolactone
USE OF SALT FORMS : Alkali metal salts of acidic
drugs like pencillin, strong acid salts of basic
drugs like atropine have more water soluble than
parent drug
41. ALTERATION OF PH OFALTERATION OF PH OF
MICROENVIRONM ENT OF DRUG:MICROENVIRONM ENT OF DRUG: by twoby two
waysways A) In situ salt formation B) additionA) In situ salt formation B) addition
of buffers eg: buffered aspirin tabletsof buffers eg: buffered aspirin tablets
USE OF META STABLE POLYMORPHSUSE OF META STABLE POLYMORPHS ::
Eg: B- chloramphenicol palmitate is moreEg: B- chloramphenicol palmitate is more
water soluble than A and Cwater soluble than A and C
SELECTIVE ADSORPTION ON INSOLUBLESELECTIVE ADSORPTION ON INSOLUBLE
CARRIERSCARRIERS : Bentonite can enhance the: Bentonite can enhance the
dissolution of poorly water soluble drugsdissolution of poorly water soluble drugs
such as indometacin,prednisone by twosuch as indometacin,prednisone by two
reasons weak physical bonding betweenreasons weak physical bonding between
adsorbate and adsorbent and hydration,adsorbate and adsorbent and hydration,
sweeling of clay in aqueous mediasweeling of clay in aqueous media
42. SOLID SOLUTIONS: a) use of solid solutions
b)use of eutectic mixtures
c)use of solid dispersions
reduces the particle size by different mechanisms
and thus enhances the bioavailability.
MOLECULAR ENCAPSULATION WITH
CYCLODEXTRIN : the beta dextrins and there
derivatives have ability to molecular inclusion complexes
with hydro phobic drugs having poor water solubility.the out
side of the host molecule have water soluble and thus
improves the aqueous solubility and dissolution rate and
thus bio availability. Eg: thiazides diuretics
43. REFERENCES
1. D.M. Brahmankar, Biopharmaceutics and
Pharmacokinetics, Vallabh prakashan, second editon, 2009
2. Shagel Wu-pong yu, bio pharmaceutics
&pharmacokinetics, fifth edition ,2005
3. www. Goggle.com
4. en.wikipedia.org
5. Amidd.inon,g.l,Lennernas, A therotical basis for a
biopharmaceutical drug classification
WWW.pubmed