The
discovery and development of new medicines is a long, complicated and an
iterative process. The portion of drug development process especially phase III
clinical trials is usually funded by industry and other private organizations.
This process is so meticulous that only four to seven percent of candidate
drugs receive approval from Food and Drug Administration (FDA). It takes
approximately 10-12 years to introduce a new drug to the market. Knowledge of
the rigorous process for drug development and of the occasional dramatic
failures opens up possibilities in the determination of new drug molecule with
increased efficacy. The drug development process is meant to ensure that
patients receive safe and effective medicine. The rapid growth in the in silico drug design has gained
significant momentum in drug discovery and development to predict the
biochemical, chemical and pharmacological activity of new drug molecule.
However, by continuing to draw on the knowledge, scientific findings and
expertise of pharmaceutical scientists, as well as applying both new and
established methods to drug development into therapeutic interventions will
undoubtedly continue to improve chances of developing new drugs for the future.
This chapter aims to summarize the main areas of drug discovery and draw
attention to the huge amount of scientific effort that goes into the production
and development of modern medicines before they reach the market place.
Keywords: Drug design, Drug discovery and
development, In silico, In vitro, In vivo, Investigation new drug, New drug molecule
INTRODUCTION
Drugs substances
are chemical ingredients intended for treating different diseases. Drug
substances are classified as inorganic substances, organic substances derived
from animal or human origin and organic substance from synthetic or
semi-synthetic or from herbal medicines [1]. Inorganic substances are chemicals
which do not have any carbon in their molecular formula; mostly they are in
salt form. Examples for inorganic substances are sodium chloride, ammonia, all
metals, etc. Organic substances derived from animal or human origin are
substances which are isolated/extracted from animal or human origin. Examples
for organic substances derived from animal or human origin are antigens,
insulin, enzymes, carbohydrates, hormones, nucleic acids, amino acids,
vitamins, fats and oil, etc. Organic substance from synthetic or semi-synthetic
or from herbals are prepared by chemical reaction or isolated/extracted from
herbal plants. Most of the polymers, active pharmaceuticals ingredients like
paracetamol, aceclofenac, metformin hydrochloride, glibenclamide etc are
organic synthetic compounds whereas compounds like vincristine, vinplastine, digitoxin,
resperine, alkaloids, flavonoids, etc., are examples for the compounds isolated
from herbal medicines/plants.
Drug discovery and development are the
two backbones of medicinal chemistry. The fundamentals of drug discovery and
development of a new drug begin from a “scientific idea”. Development of new
drug substance is centered on the market potential of the drug substance or
medical emergency need of the existing therapeutic effect. Lot of discussions
will take place from the scientific idea as a starting point in discovery
research with the ultimate goal to introduce a new drug molecule into the
market.
PRODUCT
DEVELOPMENT TEAM
Once an organization have
decided to develop a new drug substance, different groups collectively as
product development team involve in the development of new drug
Medicinal
chemist
The prime responsibility of the
medicinal chemist is to identify a basic scaffold with his chemistry knowledge
to meet the project objective, frame a synthesis process and synthesis the molecule
for further studies.
Toxicologist
Toxicologist will assess the no
toxic effect dose, LD50, ED50, therapeutic index and
toxicology of the optimized lead molecule. Pharmacokinetics and
pharmacodynamics – Concern of these team members are to assess and characterize
the new drug molecule absorption, distribution, disposition, metabolism and
excretion. Also to assess the distribution of the drug in different organs like
muscle, skin, heart, liver and kidney, etc.
Clinician
Role of the clinicians are to
assess the toxicity, pharmacokinetic and pharmacodynamics properties in human
volunteers and establish the in vitro
and in vivo correction of the new
drug molecule.
Regulatory
experts
Accountability of these experts
is to prepare the documents towards Investigation New Drug Application (INDA),
New Drug Application (NDA), Drug Master File (DMF) and commercializing the new
drug molecule into the market.
CURRENT
SCENARIO
Recently, the drug discovery and
development have stepped in new dimensional changes of drug substances from
botanicals to synthetic. For the past few decades, majority of new molecules
are discovered through synthetic chemistry process [3].
The key process in the drug discovery and
development of new drug substances are:
·
Understanding the disease
·
Target identification
·
Target validation
Different stages in the discovery and
development of new drug substances are [4]:
·
Preclinical investigation
·
Investigational new drug application
·
Phase I
·
Phase II
·
Phase III
·
New drug application
·
New drug approval
DRUG
DISCOVERY PROCESS
Synthesizing a new drug molecule is an art.
Synthesis of new drug molecules is performed by chemical transformations either
creating a new process or with the existing process. In earlier stage,
thousands of compounds were synthesized and assessed for its activity.
Nowadays, receptor targeted research have been used to assess its biological
activity.
Several key go/no-go ‘decision gates’ are
followed in the drug discovery and development process. Decision gate tool is
utilized to assess the properties of its predetermined specification/criteria
to proceed further or to the next stage of new molecule [5,6].
Steps involved in the drug discovery and
developments are [7,8]:
·
Synthesis
·
Non clinical testing
·
Non clinical pharmacology evaluation
·
Non clinical pharmacology evaluation through in vitro techniques
·
Preliminary animal pharmacokinetics
·
Preliminary drug metabolism
·
Toxicity studies
·
Non clinical pharmacology evaluation through in vivo
studies
·
In vitro and in vivo
correlation
RESEARCH
AND DEVELOPMENT
Research and development (R&D) have been
considered as the backbone of any pharmaceutical organization. The R&D
activities of the organization have a large impact and the ability to execute
the company’s targets in time. Around 10-14 years are needed to develop a new
drug molecule with an average cost of more than $800 million. Out of 10,000
compounds, only one compound will get approval by the FDA as new molecular
entity due to unacceptable toxicity observed during the drug discovery and
development stage.
The time duration for the drug discovery,
development and approval are [9]:
·
Drug discovery research: 4.5 years
·
Preclinical testing: 1 year
·
Clinical Trial - Phase I: 1.5 years
·
Phase II: 2.5 years
·
Phase III: 2.5 years
·
Submission, FDA approval and Product launch: 1.5 years
COMPUTER
AIDED DRUG DESIGN
Considering several issues in pharmaceutical
R&D sectors, different strategies are adopted in the drug discovery and
development process such as combinatorial chemistry, DNA sequencing,
High-Throughput-Screening (HTS) and computational drug design. Nowadays,
computer modeling and bioinformatics tools are utilized to improve the drug
discovery and development process, which significantly reduce the time and
resources in synthesis of drug molecules.
These computational methods consist of
computer aided biological system, biological system and chemical system.
Computer aided biological system includes – hit identification, hit to lead
selection, absorption, distribution, metabolism, excretion, optimization and
toxicity profile. Biological system includes functional proteins, monocellular
organisms, multicellular organisms, cells isolated from tissues and organs.
Chemical system includes ligand-based drug design, structure-based drug design,
Quantitative Structure-Activity Relationships (QSAR) and Quantitative
Structure-Property Relationships (QSPR) [10-12].
Determination of protein
structure
A modern approach to structural biology
utilizes as many methods as possible to decipher a convergent molecular
picture. 3D-structures are determined commonly by X-ray and neutron-diffraction
methods or NMR spectroscopy. In all cases, computer assisted data manipulation
is required but, in addition, computer modeling and bioinformatics methods help
research. In order to get a reliable, broad and good enough picture on
structure and dynamics of proteins, a careful evaluation of the experimental
data is needed by typically using a variety of techniques. The first protein
structures were determined by X-ray diffraction in the early 1950s and until
now over 80,000 structures were deposited in the Protein Data Bank [13].
Structure determination by NMR spectroscopy is also possible, but the number of
deposited structures to date does not exceed 10,000 entries.
X-ray
crystallography
One of the major drawbacks of protein
crystallography is the requirement of relatively large single crystals of the
target protein. Hence, it is often a tedious task and hard to fulfill. Once a
suitable crystal appropriate in size and quality is found, it is irradiated by
X-rays and the obtained diffraction pattern is detected and subsequently
analyzed. Using the information of primary sequence of proteins, it is further
evaluated and refined. Finally, a 3D representation of the protein molecule is
obtained and visualized by various techniques:
I.
Sample purification and crystallization
II.
Data collection
III.
Structure solution
IV.
Model building
V.
Refinement and validation
Final structures are validated by various
bioinformatics methods. Neutron diffraction is a method that requires high
thermal-neutron fluxes obtained from nuclear reactors and provides special
information on proteins. Hydrogen atoms can be precisely located, which is
almost impossible by X-ray diffraction. A diffraction experiment can be
performed on a crystal; the results can be evaluated similarly, as done for the
X-ray technique.
Nuclear
magnetic resonance (NMR) spectroscopy
NMR spectroscopy is an important method of
modern structural biology, allowing determining three-dimensional protein
structures in solution, and even in case of some proteins for which X-ray
diffraction does not provide enough result. It became an almost routine method
for the structure determination of proteins up to about 30 kDa molecular
weight. For an NMR measurement, a protein solution of at least 95 % purity is
needed, which is stable over a week and has an appropriate concentration (0.1-1
mM).
Stages involved in the in silico drug design are:
1. Determination of protein structure
2. Target structure determination along with a promising lead
3. Optimized lead molecule synthesis, new target structure determination
and its complex
4. Lead compound optimization
5.
Optimized compounds and its binding with target
specificity
The advantage of in silico studies
is the speed of execution, the low cost and the ability to reduce the use of
animals. The use of in silico methods has been an interesting strategy to
accelerate the discovery of potential new drugs. In drug discovery and development, in silico drug design procedure is
performed in two ways [14,15]. They are Structure/Receptor Based Drug Design
(SBDD) and Ligand Based Drug Design (LBDD).
Structure/receptor
based drug design
In this approach, cell signaling or metabolic
pathway is the key process for a particular disease.
Determination of
protein structure:
X-ray crystallography and NMR spectroscopy are used to determine the 3D
structure of target protein [15].
Homology modeling: In homology modeling, 3D structure of target
protein is predicted based on the sequence [11,16,17].
Protein folding: When the similar protein sequence
are not available, protein folding technique is adopted for the determination
of protein. In this technique, target proteins are identified based on
threading methods or fold recognition [15,17-20].
Ab initio (de novo) modeling: When the homologous structures of
protein are not available for comparison, ab
initio (de novo) modeling
technique is adopted. The target proteins are identified based on the sequence
[15,17,21-25].
Ligand-based drug
design (LBDD)
This approach is grounded on the previous
study results of the interaction between the small molecules and the target
proteins [15,26].
Virtual screening: New chemotype molecules are
identified based on the process of scoring, ranking and affinity from the
chemical compound databases/chemical libraries [8,17,27-31].
Two categories of virtual screening are:
1. Structure based virtual screening
2. Ligand based virtual screening
Structure
based virtual screening (SBVS)
In this screening technique, the chosen
molecule is docked with the selected target protein. Molecules will be selected
founded docked scoring and ranking, then it will be experimentally tested for
its target protein binding site [32-34].
Steps involved in the SBVS are [35]:
i.
Preparation of molecular target
ii.
Selection of compound from the database
iii.
Molecular docking
iv.
Post-docking analysis
Ligand
based virtual screening (LBVS)
This screening technique is adopted when the
receptor structural information is unable to predict. Different approaches in
this screening technique are:
·
Similarity search
·
Pharmacophore-based virtual screening
·
Quantitative structure-activity relationship
Similarity
search
Screening of the physical and chemical
similarity of the compounds in the databases.
Lead molecule is selected from the 2D score
value and 3D similar structure of compounds from the database
[11,15,17,25,36-39].
Pharmacophore-based
virtual screening
In this screening technique, pharmacophore
model is generated and assessed for its binding efficiency to a target protein
and its structural features such as H-bond donors, H-bond acceptors,
hydrophobic, aromatic, positive, ionizable groups and negative ionizable groups
[11].
Steps involved in the 3D pharmacophore model
generation are [15]:
·
Binding of the active compounds to the desired target.
a. Defining the atom types and connectivity in the 2D pharmacophore model.
b. Defining the nomenclature in the 3D pharmacophore model.
·
Identification of common feature property for binding.
·
Pharmacophore model generation.
·
Selection of best models based on the ranking of the
pharmacophore models.
·
Validation of pharmacophore models.
QUANTITATIVE
STRUCTURE ACTIVITY RELATIONSHIP
This method correlates the relationship between
molecular descriptors of the molecules of ligand and binding target relates to
its biological activity [14,40-44].
MOLECULAR
DOCKING
Molecular docking is a computer algorithm, used
to predict the binding between the ligand and the target binding sites
[11,17,45,46].
Three types of docking algorithms are used to
predict the binding between the ligand and the target binding sites [47]. They
are:
a. Rigid docking
b. Semi-flexible docking
c.
Flexible docking
Confirmation of the binding between the ligand
and protein active site is identified by Le et al. [17]:
i.
Accurate pose prediction.
ii.
Accurate binding free energy prediction.
Confirmation of the ligand in molecular docking
is confirmed by specific scoring function. Specific scoring functions are:
1. Conformational search: Conformational search in molecular docking is
determined by either systematic search or stochastic search [48,49]
2. Evaluation of binding energetics: Evaluation of binding energetics in molecular
docking is determined by Force-field based scoring function, empirical scoring
function and knowledge based scoring function [50].
3. Covalent bonds in molecular docking
4. Molecular dynamics
5. Structural water
6. Protein-protein interaction inhibitors and molecular docking [51].
MOLECULAR
LIPOPHILICITY
Molecular lipophilicity is defined as log P, it
has an important role in molecule permeability, bioavailability, toxicity and
also the interaction between the drug molecule and target site [52].
Lipinski “rule of five” [53] is used to
distinguish drug like and non-drug like molecules. Lipinski rule predicts high
probability of success or failure due to drug likeness for molecules complying
with 2 or more of the following rules:
1. Hydrogen bond donors (sum of hydroxyl and amine groups) less than 5.
2. Hydrogen bond acceptors (sum of nitrogen and oxygen atoms) less than 10.
3. A molecular weight under 500 Da.
4. A log P coefficient of less than 5.
PHARMACOKINETIC
PROPERTIES (ADME)
Pharmacokinetic parameters like absorption,
distribution, metabolism and excretions are considered during the development
stage itself to avoid any future failure. Nowadays, High Throughput Screening
techniques are utilized to assess quantitative structure-activity relationship
(QSAR) and quantitative structure-property relationship (QSPR) properties
through mathematical model to predict the pharmacokinetic parameters of the
drug molecules [17,54,55].
Development of luminescence due to the
interaction between the ligand and biological compound, its measurement is the
basic principle of HTS.
Several methods are used to measure the
luminescence. They are given below:
·
Fluorescence Anisotropy (FA)
·
Fluorescence Correlation Spectroscopy (FCS)
·
Fluorescence Intensity (FI)
·
Fluorescence Lifetime Imaging Microscopy (FLIM)
·
Fluorescence Resonance Energy Transfer (FRET)
·
Total Internal Reflection Fluorescence (TIRF)
·
Time Resolved Resonance Anisotropy (TRRA).
Other nano-bead based techniques for measuring
the luminescence are [55]:
1. Scintillation Proximity Assay (SPA)
2. Amplified Luminescence Proximity Homogeneous Assay (ALPHA)
PHYSICOCHEMICAL
PROPERTIES
Physicochemical properties of the new molecules
has important role in the pharmacokinetic parameter. Different pharmacokinetic
parameters include [56]:
·
pKa
·
LogP and LogD
·
Polar surface area
·
Lipophilicity
·
Solubility
·
Permeability
PREDICTION
OF PHARMACOKINETIC PARAMETERS INCLUDES
1. Absorption
2. Distribution - Blood-brain barrier penetration and Plasma Protein
Binding
3. Metabolism - Site of metabolism (SOM) prediction and Metabolite
prediction
4. Excretion [56-63].
Prediction
of toxicity
Damage on organism or substructure of organisms
includes cells and organs are defined as toxicity. A good drug molecule should
not produce any toxicity and to produce good therapeutic effect. Earlier stage
prediction of toxicity can help to develop a desirable drug molecule. Other
toxicity study includes acute toxicity, genotoxicity and hERG toxicity.
Five steps are generally followed to predict
the toxicity [64-66]. They are:
1. Data collection based on the relationship among the drug molecule and
the toxicity.
2. Calculation of the new molecule molecular descriptors.
3. Prediction model development.
4. Assessing the developed model performance.
5. Evaluation.
Lead molecule is optimized from the toxicity
prediction. Once the lead molecule is optimized, the real process of drug
development will start.
DRUG
DISCOVERY AND DEVELOPMENT PROCESS
Synthesis
Medicinal chemist will prepare the final
synthesis step and perform the reaction in batch to synthesis the optimized new
drug molecule for further studies. Synthesis of initial quantity in batch scale
is depends on its complexity, lengthy synthesis process and yield.
Crystallization
Crystallization is a process of separation and
purification of new drug molecule, which involves formation of nuclei and
molecular aggregation in a solution through diffusion process. Sequences
involved in the crystallization are super saturation, nucleation and crystal
growth. Approximately, 1,020 molecules are arranging in an order by themselves
to form a definite as crystal lattice. These crystal forms differs in its
physicochemical properties also its bioavailability and stability [67,68].
Evaluation
of physicochemical properties
Once synthesis and crystallization
(purification) process are completed, the synthesized compound will be
evaluated for its physicochemical properties. The physicochemical properties
include [69]:
1. Physical form – Assessing its crystalline polymorph
2. Organoleptic properties.
3. Melting point
4. Solubility profile
5. pH, pKa or pKb
6. Specific gravity or bulk density
7. Spectroscopic character
8. Isomeric composition
Non-clinical
evaluation
Non clinical pharmacological evaluation [2] is
performed in animal models to assess its:
1. Safety and efficacy
2. Mechanism of action
3. Pharmacodynamics properties
4. Preliminary protein binding
5. Dose fixation
6. Cellular uptake and membrane transport
IN VITRO
STUDIES
Recently, gene based diagnostic test kits are
used during in vitro studies. For an example, to measure the HIV resistance,
HIV-1 TruGene Assay is used which can provide options for AIDS patients during
treatment.
Metabolism is the key determinant to produce
the therapeutic efficacy. Too rapid metabolism of drug leads to lose its
therapeutic efficacy. Cytochrome enzymes like CYP2D6, CYP2C9, CYP3A4/5, CYP2C19
and CYP1A2 are the key enzymes in human liver. Around 50% of small molecule
drugs are metabolized by CYP3A4 enzyme. For in vitro metabolism studies, the
main metabolism enzyme cytochrome P450 from liver is used due to its ready
availability. For metabolic profiling, liver slices from human and animal
species can be used. Gastrointestinal mucosa, brain, placenta, skin and kidney
are used as non-hepatic tissues. Non- cytochrome P-450 enzymes are responsible
for the reaction such as glutathione conjugation, acetylation, sulfation and
glucuronidation [70].
ANALYTICAL
METHOD
To quantify the concentration of new molecule
in the biological sample, a suitable bioanalytical method needs to be developed
with good selectivity, sensitivity and reproducibility. When response
components are unavailable to quantify the new molecule, different
physiological and pharmacological biomarkers are used during validation studies
[71-73].
PRELIMINARY
PHARMACOKINETIC STUDIES
Developed bioanalytical method is used to
assess the preliminary pharmacokinetic properties of the new molecule.
Preliminary pharmacokinetic property includes absorption, distribution,
metabolism and excretion. Organ distribution and toxicity studies are also
performed in liver, fat, kidney, muscle, skin, heart and urine [74].
IN VIVO
STUDIES
When an initial clinical study results proves
that the new drug molecule is safe, investigator can submit the investigational
new drug application. Investigational new drug application comprises of drug chemical
composition, preparation procedure, qualitative and quantitative analytical
method, preclinical and clinical study.
REVIEW
OF THE IND
Once investigational new drug application is
received by FDA, FDA reviews the IND application. Different review committee
members review the chemistry, pharmacological, toxicological and clinical
efficacy of the new drug molecule. FDA gives an approval or clinical hold for
clinical trials from the constructed review report [76,77].
CLINICAL
TRIALS
In drug discovery and development process,
clinical trial is the most critical and demanding phase. Clinical trial
programme will be carefully executed in larger population to assess the drug
efficacy.
Clinical trial is performed in three stages.
Phase 1: Human volunteers are exposed to a
single rising dose study, a short multiple dose study and food interaction
study.
Phase 2: Human volunteers are exposed to a dose
ranging study.
Phase 3: Human volunteers are exposed to double
blind comparative studies with registered compounds [78-81].
A survey of the drug development database
suggest that the success rate for Phase III is decreased from 40% during
1999-2003 to 18% during 2011-2014 (failure in Phase III is increased to 50%).
Moreover, the investment in Phase III is huge and more expensive when compared
to other phases due to longer study duration, unpredicted pharmacokinetic and
therapeutic effect among the human volunteers. To overcome the unpredicted
pharmacokinetic and therapeutic effect, pharmaceutical organizations adopt
different strategies to assess the pharmacokinetic parameters during in vitro and in vivo studies [82,83].
NEW
DRUG APPLICATION (NDA)
After observing the results of clinical trials,
pharmaceutical organization can submit new drug application. New drug application
comprises of the chemistry, composition, strength, purity, non-clinical and
clinical test results and its interpretation data, preparation procedure,
qualitative, quantitative analytical methods and draft label of the new drug
molecule.
The draft label consists of:
Ø Product description
Ø Clinical pharmacology
Ø Indications and usage
Ø Contraindication and Warnings
Ø Adverse reactions and Precautions
Ø Drug abuse and dependence
Ø Dosage
NDA
review
Once new drug application is received by FDA,
the FDA starts to review the NDA application. Different review committee
members assess the chemistry, pharmacological, toxicological, clinical
efficacy, statistical, biopharmaceutical and microbiology (if applicable) of
the new drug molecule. After review by the expert committee members, a review
report will be prepared and submitted. The review report includes written
evaluation, observation, conclusions and recommendation/non recommendation
regarding the new drug molecule [84-86].
Pre-approval
inspection
The investigators from FDA will visit the
applicant manufacturing premises with respect to their statements. After
inspection by the FDA investigators, recommendations of the investigators, the
Center for Drug Evaluation and Research (CDER) will issue an action letter stating
an approval/approvable/not approvable. Any issues or deficiencies in the
premises are addressed to the applicant before the approval and a time frame is
provided for resubmission of the application by the applicant [4].
MANUFACTURING
PROCESS AND PROCEDURE OF NEW DRUG SUBSTANCE
Starting
materials and reagents
The key starting materials and reagents which
are used for the synthesis should be commercially available with desired
physical and chemical properties and must meet the desired specifications like
USP, NF and ACS specifications.
Preparation
process
Synthesis: A standard procedure
with a complete diagrammatic flow chart for the preparation of drug substance
with the desired purity must be given. Diagrammatic flow chart must provide
quantity of raw materials, reagents, catalyst, equipment, process condition
with isolation and purification of the new drug molecule if any.
Process
control: A detailed process control is needed to be provided to ensure the
quality (intermediate specification), quantity and purity of the material
synthesis.
Quality
control: Quality of the products is verified through a quality control process.
Quality control tests are performed to ensure the physicochemical property of
the drug substances with the desired quality control specification. A detailed
specification with the acceptance criteria for impurity/degradation products
and residual solvents is needed to be provided. If the product is manufactured
in aseptic condition, microbiological quality control process and procedure
needed to be provided. Physicochemical property of the drug substance includes
description, physical properties, identification, impurity profile and assay.
ANALYTICAL
METHODS
Analytical methods and its procedure are the
most key parameters to ensure the quality of the product. When there is
unavailability of pharmacopoeia monograph, it is sole responsibility of the
manufacturers to develop of a suitable analytical method and its validation
[87,88].
Manufacturing
process controls
Manufacturing process controls include process
validation, air handling unit and cleaning validation.
Process
validation
Process validation is a systematic evaluation
of the critical process in the manufacturing to ensure the drug safety and
quality in a reproducible one [89].
Air
handling unit
Microorganisms are present everywhere in the
earth; it can damage any type of organic or inorganic compounds. A specified
environmental monitoring system includes air filtration, heating, ventilation
and air conditioning can provide a clean room and aseptic facility free from
microorganisms for the manufacturing of drug substance. Environmental
monitoring system also includes desired airflow, temperature, humidity, water
and compressed gas to ensure the environment free from microorganisms [90,91].
Cleaning
validation
Cleaning validation of an Active Pharmaceutical
Ingredient (API) equipment/facility is important to prevent the cross
contamination. A detailed cleaning validation programme includes selection of
suitable cleaning agent, cleaning method, sampling techniques, recovery of the
residue, analytical method, acceptance criteria, detection of residues and a
cleaning report. Cleaning validation ensures that prepared products are free
from the previous batch materials, unintended contamination materials,
microbiological contamination as well [92,93].
Container
and closure system
Suitable container and closures are selected
grounded on the results of stability study in order to ensure the suitability
and stability of the drug substance.
Product Label - Label of the product has an
important role to guide the physician. Product label provides information about
the appropriate dose, dosage regimen and adverse effects which are observed
during the clinical trials.
Drug
master file (DMF)
DMF is a document which provides confidential
information regarding the manufacturing facilities, process, packaging and
storage of the drugs.
OVERVIEW
OF DRUG DISCOVERY AND DEVELOPMENT
Recently, drug discovery and development
process have undergone enormous changes. After lead molecule identification and
optimization, it is evaluated for its physicochemical properties followed by
the determination of its therapeutic activity by in vitro and in vivo
models.
There are four stages involved in the drug
discovery and development.
1. Assessment of toxicity, preliminary pharmacokinetics and its therapeutic
effect of the optimized lead compound.
2. Optimizing the dosage form founded on the pharmacokinetic properties.
3. Assessment of its therapeutic activity in human volunteers and patients.
4. Assessment of other toxicities like carcinogenicity, mutagenicity and
reproductive toxicology study, etc., is performed.
CONCLUSION
Development of new drug substances from
botanicals to chemical synthetic process is a prime scientific development in
the modern health care. Early drug discovery and development estimated that
only 1 out of 10,000 screened compounds is approved by the FDA and it takes
around 20 years to introduce a drug molecule into the market with an average
cost of more than $800 million. Considering this huge cost, pharmaceutical
organization have adopted new techniques in the drug discovery and development.
In this review, early studies for the identification and validation of
therapeutic targets and the in silico
and high-throughput screening approaches that contribute to lead drug candidate
selection which will advance the development process were briefly discussed.
Also reviewed were the steps involved in the process of new drug development.
As an outcome, these would result in the expansion and validation of several
alternative methods that can be adopted and recommended by the main
international regulatory agencies. Further, lead molecules can be identified
and optimized in short duration to avoid further failures of the drug from the
bench to the market.
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