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Applicaton of biopharmaceutics
in new drug development
Vrushali V. Sonawadekar.
1st year M-PHARM
Dept. of pharmaceutics
Kle college of pharmacy Belagavi..
• Importance of bio pharmaceutics in development
• Pre-clinical testing
• Clinical trials
• Post clinical surveillance
• Advanced clinical development
• The task of discovering & developing safe & effective
drug is gaining lots of importance these days.
• It is becoming an increasingly challenging undertaking.
• Facts of drug discovery & development :
1. Time :10-15 years
2. Cost :800 millions-1 billions
3. Drug tested :5000-10000 molecules
4. Subject tested :1000-5000
5. Drug approved :1
• Modern discovery is the product of cooperation
• Both public & private organization play an unique
roles in translating basic research into medicine
• Major biopharmaceutical companies are the primary
source of R & D funding of new medicines.
• Smaller companies conduct basic research , drug
discovery , preclinical experiments & in some cases
• The national institute of health (INH) provides
leadership & funding stimulate basic research &
early stage development of technologies.
Importance of Biopharmaceutics in
the Overall Development Process
• Biopharmaceutics is an integral component of the overall
development cycle of a drug
• Evaluation begins during the drug discovery process, proceeds
through compound selection, preclinical efﬁcacy and safety
testing, formulation development, clinical efﬁcacy studies, and
post approval stages.
• At each stage, biopharmaceutical scientists interface with in
multiple disciplines including discovery chemistry and biology,
drug safety assessment, clinical development, pharmaceutical
development, regulatory affairs, marketing, and manufacturing
• The ensuing section will discuss the general activities
and impact at each stage of development and
provide an overall view of the role of
biopharmaceutics at various stages of drug
Discovery and Preclinical
• The preclinical development stage encompasses
aspects of both drug discovery and drug
• Depending on the desired therapeutic action, the
target blood concentration–time proﬁle must be
considered with respect to Cmax, tmax, AUC,
clearance, accumulation, and dose proportionality.
• Species effects are also an important consideration
• The physical–chemical properties of the drug candidate,
such as solubility, sta- bility, and lipophilicity, inﬂuence the
in vivo performance and must be considered for any drug
• Preclinical ADME studies in vivo using various animal
models are also necessary to assess blood concentration–
timeproﬁles, AUC, Cmax, tmax, dose proportionality,
accumulation upon multiple dosing or enzyme induction.
• Stability of compounds is another factor that must be
evalu- ated as it affects the integrity of the material being
dosed, could potentially lead to generation of degradants
with distinct pharmacologic action or toxicity, and also
impacts the handling and shelf-life of a pharmaceutical
• Discovery involves followings :
1. Pre-discovery : Understanding the disease
2. Target identification :choose molecules to
target with a drug.
3. Target validation : Test the target & confirm its roles in
4. Drug discovery : find a promising lead compound that
could becomes a drug.
5. Early safety tests : perform initial tests on lead .
6. Lead optimization : alter the structure of lead
compound to improve properties .
• 5000-10000 molecules are selected & tested.
• Scientists test Absorption , Distribution ,
Metabolisms , Excretion & Toxicological (ADME/Tox)
properties or pharmacokinetics.
• Successful drug must be :
1. Absorption into the bloodstream
2. Distribution to the proper site of action in the body.
3. Metabolized efficiently & effectively
4. Successfully excreted from the body
5. Demonstrated to be not toxic.
• With more optimised compounds in hand
researchers turns their attention to testing them
extensively to determine if they should move on to
testing in humans.
• Scientists carry out in vitro & in vivo tests
• They try to understand a drug’s kinetics toxicity &
• The U.S Food & Drug Administration (FDA) requires
extremely thorough testing before the candidate
drug can be studied in humans.
• Around 250 drugs are tested in pre clinical phase of which at least 5
molecules are selected as “candidate drug”
• After selection of candidate drugs sponsors file a IND
(Investigational New Drug) Application to FDA.
• The Application includes :
1. The results of the pre clinical work
2. The candidate drug‘s chemical structure &
3. How it is thought to work in the body
4. A listing of any side effects &
5. Manufacturing information
• The IND also provides a detailed clinical trials plan that outlines how
where & by whom the studies will be performed.
• In addition to the IND application , all clinical trial
must be reviewed & approved by the “institutional
review board” (IRB) at the institutions where the
trials will takes place.
• This source includes the developments of
appropriate informed consent which will be required
of all clinical trial at any time if problems arise.
• The company sponsoring the research must provide
comprehensive regular reports to the FDA & the IRB
on the progress of clinical trials.
• This phase is the longest one in drug development from 2-10
• A suitable clinical design is developed . These includes
1. Placebo controlled trials
2. Randomized trials
3. Double blinded studies
• Clinical trials comprise of three phases
1. Phase 1
2. Phase 2
3. Phase 3
4. Phase 4 i.e pre-marketing surveillance
Phase 1 trials
• The candidate drug is tested in people for the first time .
• These studies are usually conducted with 20 to 100 healthy
• Usually last 6 months to 1 year (30% of drug fail phase 1
• A clinical candidate must be tested in formal animal safety
studies in multiple species in order to establish a safety proﬁle
and provide guidance on the choice of clinical doses.
• Solutions are highly desir- able for dosing because they are
homogeneous systems that are easy to administer to animals
(particularly rodents), offer dose ﬂexibility, and have the
potential for maximizing in vivo exposure by avoiding issues
with dissolution. 15
However , poorly soluble compounds may lack sufﬁcient
solubility to prepare highly concentrated solutions, and
pharmaceutically acceptable non-aqueous vehicles or
suspensions must be used if a liquid vehicle is necessary.
• used to determine
1. Pharmacokinetics data
2. Pharmacodynamics data
3. Max. tolerated dose
4. Adverse reactions profile
Phase 2 trials
• In phase 2 trials researchers evaluate the candidate drug’s
effectiveness in about 100 to 500 patients with the disease or
condition under study.
• Usually 2 years (37% of drugs fails phase 2 testing)
• Used to know
1. Preliminary evidence of efficacy
2. Pharmacodynamic effects in patients
3. Optimal dosage ranges & dosing schedule
• Phase 2 trials are followed by a meeting with FDA to obtained
agreement on phase 3 adequate & well controlled study design &
Phase 3 trials
• In phase 3 trials researchers study the drug candidate in a
larger number (about1000-5000)of patients .
• Usually last 3 years ( 6%fail phase 3 testing)
• Used for
1. Confirmation of efficacy
2. Establishment of complete safety profile
3. Base of regulatory information (labeling)
4. Assessment of risk / benefit
• Phase 3 trials are both the costliest & longest trials.
• Hundreds of sites around the world participate in the study
to get a large & diverse group of patients.
• Coordinating all the sites & the data coming from them .
• In addition to these trials additional special trials
should be performed to evaluate drug in :
1. Special populations
3. Special conditions
4. Special toxicities
5. Addition potential
• Research on new medicines continues even after approval .
• These studies are generally termed as phase 4 trials.
• As a much larger no. of patients begin to use the drug ,
companies must continue to monitor it carefully & submit
periodic reports , including cases of adverse events ,to the
• These trials can be set up to evaluate long term safety or how
the new medicines affects a specific sub group of patients.
• Yearly safety reports must be filed with the applicable
regulatory agencies as long as a drug remains on the market.
• If safety concerns aries the FDA may demands withdrawal of a
from the market anytime.
Advanced clinical development
• As a compound moves from Phase I into Phase II and
eventually into Phase III, the objectives of the clinical
development program evolve from primarily safety
and PK to safety and efﬁcacy.
• PK studies conducted in Phase I and II are used to
establish a body of knowledge surrounding the
intrinsic properties of the medicinal agent (e.g., clear
ance) as well as the dependency of the performance
on the actual product used.
• The discovery & development of new
medicines is a long completed process.
• Research based pharmaceutical companies
are committed to advancing science &
bringing new medicines to patients.
• Increased support from govt & organisation
may helps in development safer & cost
Application of biopharmaceutics
in designing of novel drug delivery
• The term drug delivery covers a broad range of
techniques used to get therapeutic agents into the
• The frequency of administration or the dosing interval
of any drug depends upon its half life or mean
residence time (MRT) & its therapeutic index .
• When drug is delivered as a conventional dosage form
such as a tablets , the dosing interval is much shorter
than the half life of the drug resulting in a no. of
limitations associated with such a conventional dosage
1. Poor patients compliance – increased chances of
missing the dose of a drug with short half life for
which frequent administration is necessary
2. The unavoidable fluctuations in the drug
concentration may lead to under medication or over
medication as the Css values fall or rise beyond the
3. The fluctuating drug levels may lead to precipitations
of adverse effects especially of a drug with small
therapeutic index whenever over –medication occurs.
• There are two ways to overcomes such a
1. Development of new , better & safer drug
with long half –lives & large therapeutic
2. Effective & safer use of existing drugs
through concepts & techniques of novel drug
Factors in the design of novel drug
• The basic rationale of a novel drug delivery
system is to optimize the biopharmaceutics ,
pharmacokinetics & pharmacodynamics
properties of a drug in such a way that its
utility is maximised through reduction in side
effects & cure or control of disease condition
in shortest possible time by using smallest
quantity of drug , administered by the most
A. Biopharmaceutics characteristics of a drug in
the design of novel drug delivery system -
• The performance of a drug presented as a
novel delivery system depends upon its-
1. Release from formulations
2. Movement within the body during its
passage to the site of action.
• The desired boiphamaceutics properties of a drug to be
used in novel drug delivery system are discussed below
1. Molecular wt of the drug : lower the mol wt , faster &
more complete the absorption . The mol size is 150
daltons for spherical compounds & 400 daltons for linear
compounds. Eg : proteins & peptides
2. Aqueous solubility of the drug – a drug with good aq.
Solubility , especially pH dependent , serves as good
candidate for novel drug delivery system eg:
pentoxifylline. lower limit of solubility of drug is more
than 0.1 mg/ml
3. Apparent partition coefficients / lipophilicity of the drug .-
greater the partition coefficients of a drug , greater its
lipophilicity & thus , greater its rate & extent of
4.Drug permeability : three major drug characteristics
that determine the permeability od drug for passive
transport across intestinal epithelium are –
a. lipophilicity , expressed as Log P .
b. Polarity of drug which is majored by the no. of H bond
acceptors & no. of H bonds donors on the drug
c. Molecular size
5. Drug stability : drugs are stable at both gastric &
B. Pharmacokinetics characteristics :
1. Absorption rate: high.
2. Elimination half life: the drug with half life in the
range 2- 4 hrs. make good candidate for such a
system. Eg. Propranolol.
3. Rate of metabolism: a drug which is extensively
metabolised is suitable for novel drug delivery system
as long as the rate of metabolism is not too rapid.
4. Dosage form index: it is defined as the ratio of Css MAX.
to Css,min. since the goal of novel formulation is to
improve therapy by reducing the dosage form index
while maintaining the plasma drug level within the
therapeutic window, ideally , its value should be as
close to one as possible.
C. Pharmacodynamic properties:
1. Drug dose: dose strength of 1g is considered
2. Therapeutic range: wide.
3. Therapeutic index: wide.
4. Plasma concentration – response relationship:
drugs such as reserpine whose pharmacological
activity is independent of its concentration are
poor candidates for novel drug delivery system.
Pharmacokinetic principles in a
design of novel drug delivery system
• CT is the target concentration to be maintained for T hour.
• Rate of elimination = K.CT.Vd or CT.Vd
• Where K is the elimination rate constant of the drug.
• V is the apparent volume of distribution.
• Rate of absorption, Ka Xa should be equal to the rate of elimination
to maintain constant concentration. So ,
Ka Xa = K. CT Vd
• Then rate of release should be equal to the rate of absorption and
rate of elimination. So,
Rate of release, Kr = K. CT Vd
Maintainence dose = rate of release x duration to be maintained
= K. CT Vd T
tmax = Log Ka
Where Ka is absorption rate constant
Loading dose = CT Vd e-Ktmax
• Where F is bioavailability (fraction)
• Above is on the basis that drug confers one compartment
• Equation to express plasma concentration of
C = K0 (e-KT -1) e-Kt
• Where K0 is zero order release rate
• ‘T’ is time of total release
• ‘t’ is anytime at which concentration is measured
• ‘t’ can be less than or equal or more than ‘T’
Applications of pharmacokinetics in
• To understand the process of absorption, distribution, elimination of
drug, which affects onset and intensity of biological response.
• To access plasma drug concentration response to given dose which
is considered as more appropriate parameter than intrinsic
• In design and utilization of In-vitro model that can evaluate
dissolution characteristics of new compound formulated as new drug
formulations and establish meaningful IVIVC.
• In design and development of new drug and their appropriate dosage
• In safe and effective management of patients by improving drug
• To understand the concept of bioavailability which has been used to
evaluate and monitor in vivo performance of new dosage forms and
• To carry out the bioavailability and bioequivalence tests.
• We can use the pharmacokinetic principles in the development of
the various NDDS.
Eg: The drug with short half life about 2-6 hrs can be formulated as
controlled release drugs by using polymers.
The lower bioavailability of the drugs can be increased by using
several components like ß-cyclodextrin.
• List of drug carriers in NDDS:
Nanosomes, Liposomes, Niosomes, Proniosomes, Vesicular drug
delivery system, Cubisomes, Aquasomes, Pharmacosomes,
Miscelles, Nanoparticles, Nanosphere, Microsphere, Microparticle,
Dendrimer, Microemulsion, Transferosomes, Nanosuspension,