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Answer:
METHOD METHOD
TRANSFER VALIDATION
Fig.1.0
2. In designing a medicine, what are the primary factors to consider. Give their
importance.
Answer:
DRUG FACTORS:
BIOPHARMACEUTICAL THERAPEUTIC PREFORMULATION
ASPECTS CONSIDERATION
• Organoleptic
• Route of • Nature of clinical
properties
indication
Administration • Bulk
• The way disease or
• Pharmacokinetic characteristics
illness is treated
parameters • Solubility
analysis
• Stability analysis
Fig. 1.1
Following qualities of features are required in drug and dosages form design:
1. Drug would produce specifically desired (therapeutic) effect.
2. Be administered by most desired route at minimal dose and dosing frequency
3. Drugs have short onset and optimum duration of activity, without any side
effect.
4. Would be completely eliminated from the body efficiently without any residual
effect.
5. Pharmaceutically dosage forms should be elegant, physically, and chemically
stable at various conditions of use and storage.
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BIOPHARMACEUTICAL ASPECTS
A route of administration varies with pharmacokinetic parameters of drug, such
as, absorption, distribution, metabolism, and elimination (ADME). Drug is
administered into body by various routes such as oral, topical, parenteral,
respiratory (inhalation), rectal, nasal, ear, and eye. According to drug candidate
pharmacokinetic profile (ADME) and type of illness (disease condition), route of
administration is preferred.
THERAPEUTIC CONSIDERATION
Nature of clinical indication, disease/illness for that drug is intended is an
important factor for selection of dosages form and route of administration. In case
of emergency sublingual, an injection is given. In infants: Liquid drops, children’s:
Liquid dosage forms (e.g., syrup), in geriatric and patients suffering from
swallowing difficulties chewing tablets is preferred.
PREFORMULATION PARAMETERS
Physicochemical characterization
I. Organoleptic properties
DISCOVERY : RESEARCH
1. Pre-Clinical
During pre-clinical testing, lead compound was synthesized and modification
in their structure was done to improve its pharmacokinetic properties.
Absorption, distribution, metabolism and elimination aspects were enhanced to
established safety and efficacy. The lead compound must undergo also series of
assays and experiments to improve its specificity and selectivity. These assays
and tests were done using animal test samples since it is still in preclinical phase.
2. Clinical
The central role of Drug Metabolism and Pharmacokinetics in drug discovery
is to contribute to the optimization of compounds for man by balancing the
properties associated with drug gastrointestinal absorption (for orally delivered
therapies), distribution, clearance, elimination and DDI potential as rapidly and
cost effectively as possible. This can be achieved from a consideration of
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physicochemical properties and data obtained from in vitro assays with human-
derived material.
1. IN-PROCESS
In a manufacturing plant, In-process control methods for the manufacture of API
and dosage forms are key components of quality control. These methods ensure
that a production reaction step conducted by trained operators within the entire
validated process will produce a quality chemical entity in the expected yields.
2. INTERMEDIATES
Pharmaceutical intermediates are the chemical compounds that serve as
building blocks used in the production of active pharmaceutical ingredients.
During the manufacturing or synthesis of the API, pharmaceutical intermediates
are produced. The produced pharmaceutical intermediates will then under
changes in their molecular level and several processing before they will become
an active pharmaceutical ingredients.
3. IMPURITIES
In drug manufacturing especially the in manufacturing API, impurities must be
controlled. Impurities are the unwanted qualities of a drug which offer no
therapeutic effects. These impurities sometimes are potentially toxic.
4. CLEANING
Cleaning is also important in drug manufacturing. Before the production
proper, the trained personnel must see to it that all raw materials are clean or
have undergone cleaning before entering the production. Cleaning also is vitally
applicable to the equipment, premises, and personnel. The goal of cleaning is to
avoid contamination during the production.
5. FINAL API
After intermediates were produced during the making of API, these will be used
since intermediates are the building blocks in API production. The final API will
then undergo several tests and process to remove impurities, improve stability
and quality. Therefore final API are those chemical compounds ready for drug
designing which includes the making of dosage forms, etc.
6. STABILITY
In the manufacturing API and dosage forms, stability is one of the factor to be
considered. The purpose of stability testing in drug development is to provide
evidence on how the quality of an active substance or pharmaceutical product
varies with time under the influence of a variety of environmental factors such as
temperature, humidity, and light.
7. DISSOLUTION
Dissolution testing is a requirement for all solid oral dosage forms and is used
throughout the development life-cycle for product release and stability testing. It
is a pivotal analytical test used for detecting physical changes in an active
pharmaceutical ingredient and formulated product. At the early stages of the
drug development process, in-vitro dissolution testing underpins the optimization
of drug-release from a given formulation. The effectiveness of an oral dosage
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form depends upon the intrinsic ability of the drug to dissolve in the fluids of the
gastrointestinal tract prior to being absorbed into the circulation. Therefore, the
rate of dissolution of the tablet or capsule is pivotal to this process.
8. EXCIPIENTS
Excipients are crucial to drug delivery within the body. Generally, an excipient
has no medicinal properties. Its standard purpose is to streamline the
manufacture of the drug product and ultimately facilitate physiological absorption
of the drug. Excipients might aid in lubricity, flowability, disintegration, taste and
may confer some form of antimicrobial function. Selecting the appropriate
excipient to support the design of your pharmaceutical formulation is an
important step in the drug manufacturing process.
9. UNIFORMITY
Drug-substance uniformity is an important consideration for the final step in
the manufacture of drug substance/active pharmaceutical ingredient. Uniformity
studies are necessary to ensure that the entire contents of the batch are
homogenous and that the drug substance specification sample is representative
of the batch.
10. LEACHABLES
A chemical species that has migrated from packaging or other components
into the dosage form under normal conditions of use or during stability studies.
Leachables are substances identified in a defined laboratory regimen by
simulating use conditions.
11. PACKAGING
Packaging is an important component in the development of various drugs, as
it can greatly affect drug stability and safety. Packaging material is chosen on the
basis of its efficacy and other characteristics that enable it to preserve the
quality, potency, and safety of the pharmaceutical products.
12. ASSAY
Assay is a procedure for the examination or determination of quality or
strength of a substance. An assay procedure is generally employed to evaluate
an intensive property of the measured entity, called "analyte". It is expressed in a
relevant measurement unit like density, molarity, etc.
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Quercetin
II. CHOOSING A One of the crucial steps in drug The chosen lead compound
CANDIDATE FOR development is the selection of the was Flavanoid which is
DRUG most optimal candidate (ex. lead specifically quercetin. This is
DEVELOPMENT compound with the best chance of due to the ADMET properties.
clinical success). In vitro and in vivo Below are the results
studies was conducted to permit concerning the properties of
further selection of lead compound quercetin.
candidates with desired ADMET
(absorption, distribution, metabolism, Quercetin is a polyphenolic
excretion, toxicology) properties as secondary metabolite that
well as pharmacology and efficacy to belongs to the flavonol class of
assist in the prediction of clinical flavonoids. It is characterized
‘drug-like’ properties. Completion of by a benzo-(γ)-pyrone skeletal
the drug candidate selection studies structure with C6-C3-C6
will provide the data to support the carbon framework, consisting
nomination to ‘clinical candidate’ of of two benzene rings, A and B,
the best compound within a list of linked by a three-carbon
potential candidates. It is key to pyrone ring C. Quercetin is
eliminate potential drug candidates referred to as
that are likely to fail in clinical trials as pentahydroxyflavonol due to
early as possible in their development the presence of five hydroxyl
(‘Fail fast and cheap’). groups on its flavonol skeletal
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Prenylflavonols are an
important group of molecules
belonging to the flavonol
subclass. They are well-known
for their wide range of
biological activities, such as
antioxidant, antibacterial, anti-
inflammatory, and anticancer
properties. Structurally, in C-
prenylflavonols, prenyl groups
are attached to the carbon
atom of the flavonol skeleton.
In the past few years,
prenylated quercetin analogs,
such as solophenol D and
uralenol, have gained a lot of
attention due to their
antibacterial properties. It has
been reported that prenylation
may enhance the biological
functions of quercetin by
increasing its hydrophobicity
and bioavailability.
Molecular Mechanisms of
Quercetin
Quercetin is used for
therapeutic purposes in
various disorders due to its
antioxidant capability The
reactive oxygen species (ROS)
scavenging activity is
attributed to a change in OH−
ions, which has a relation to
electron exchange. Catechol
oxidative agents, such as
semiquinones and quinones
formed due to quercetin, alter
redox homeostasis and inhibit
primary positive effects. In
vitro study predicted that due
to this special feature
quercetin has a protective role
in the nervous system. In the
current scenario, the
neuroprotective activity of
quercetin cannot be ignored
and additional in vivo studies
should be investigated with
different humanized animal
models to translate the
efficacy. Quercetin exerts its
antioxidant activity by
competitively inhibiting the
xanthine oxidase enzyme and
noncompetitively blocking the
xanthine dehydrogenase
enzyme. The inhibitory
capabilities are due to its
flavonoid structure rather than
to its antioxidant potential.
III. DRUG TARGETS The term "biological target" is HMGB1 Signaling Pathway
AND TOOLS DURING frequently used in pharmaceutical High-mobility group box
PRECLINICAL research to describe the native protein 1 (HMGB1) is a nuclear
DEVELOPMENT protein in the body whose activity is protein which is highly
modified by a drug resulting in a preserved. It is secreted by the
specific effect, which may be a action of macrophages
desirable therapeutic effect or an previously activated and it
unwanted adverse effect. In this works as a crucial “late”
context, the biological target is often facilitator of fatal endotoxemia
referred to as a drug target. The most and sepsis formation. The
common drug targets of currently HMGB1 protein, which is
marketed drugs include: present outside the cell, can
motivate the release of tumor
1. PROTEINS necrosis factor-α (TNF-α),
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expression of intercellular
adhesion molecule-1 (ICAM-1)
in the JAK/STAT cascade
pathway. Also, quercetin
blocked the activation of
inflammatory cytokine
interleukin-6 and interferon-γ.
It was reported that LPS-
induced STAT1 activation was
inhibited by quercetin in
combination with its profound
inhibitory effects on iNOS and
NF-κB expression, which are
persistently involved in
activation of interleukin-2 (IL-2)
8. ROLE OF THE Current Federal law requires that a The IND application was
FOOD AND DRUG drug be the subject of an approved approved by the FDA and is
ADMINISTRATION marketing application before it is ready for product formulation
AND OVERVIEW OF transported or distributed across and clinical trails.
THE state lines. Because a sponsor will
INVESTIGATIONAL probably want to ship the
NEW DRUG(IND) investigational drug to clinical
PROCESS investigators in many states, it must
seek an exemption from that legal
requirement. The IND is the means
through which the sponsor technically
obtains this exemption from the FDA.
During a new drug's early preclinical
development, the sponsor's primary
goal is to determine if the product is
reasonably safe for initial use in
humans, and if the compound exhibits
pharmacological activity that justifies
commercial development. When a
product is identified as a viable
candidate for further development, the
sponsor then focuses on collecting the
data and information necessary to
establish that the product will not
expose humans to unreasonable risks
when used in limited, early-stage
clinical studies.
FDA's role in the development of a new
drug begins when the drug's sponsor
(usually the manufacturer or potential
marketer), having screened the new
molecule for pharmacological activity
and acute toxicity potential in animals,
wants to test its diagnostic or
therapeutic potential in humans. At
that point, the molecule changes in
legal status under the Federal Food,
Drug, and Cosmetic Act and becomes
a new drug subject to specific
requirements of the drug regulatory
system.
There are three IND types:
• An Investigator IND is submitted
by a physician who both initiates
and conducts an investigation,
and under whose immediate
direction the investigational
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drug is administered or
dispensed. A physician might
submit a research IND to
propose studying an
unapproved drug, or an
approved product for a new
indication or in a new patient
population.
• Emergency Use IND allows the
FDA to authorize use of an
experimental drug in an
emergency situation that does
not allow time for submission of
an IND in accordance
with 21CFR , Sec. 312.23 or
Sec. 312.20. It is also used for
patients who do not meet the
criteria of an existing study
protocol, or if an approved study
protocol does not exist.
• Treatment IND is submitted for
experimental drugs showing
promise in clinical testing for
serious or immediately life-
threatening conditions while the
final clinical work is conducted,
and the FDA review takes place.
There are two IND categories:
• Commercial
• Research (non-commercial)
The IND application must contain
information in three broad areas:
• Animal Pharmacology and
Toxicology Studies - Preclinical
data to permit an assessment as
to whether the product is
reasonably safe for initial
testing in humans. Also
included are any previous
experience with the drug in
humans (often foreign use).
• Manufacturing Information
- Information pertaining to the
composition, manufacturer,
stability, and controls used for
manufacturing the drug
substance and the drug
product. This information is
assessed to ensure that the
company can adequately
produce and supply consistent
batches of the drug.
• Clinical Protocols and
Investigator Information -
Detailed protocols for proposed
clinical studies to assess
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hexanoyl)cyclomaltoheptose) was
used as core polymer for
nanocapsules. These nanocapsules
were then coated with the cationic
polymer chitosan to improve the
cellular uptake and interaction with
biological membranes and penetration
through intestinal mucosa for
absorption of CPT and reaching the
circulation. Nanocapsules were
characterized for their in vitro
properties followed by cell culture
studies evaluating anticancer efficacy
and permeability in comparison to CPT
in solution form.
COMMERCIALIZATION STRATEGIES
Targeted stakeholders
Today, pharmaceutical companies
that are launching new products have
less opportunity to ‘test, learn from
and refine’ messages due to the rapid
pace at which new therapies are
entering the market. Even when the
science and clinical results are in a
product’s favor, getting a product’s
messaging and services right—the
first time—can make or break the
success of its commercial launch.
Wrap-around services
Manufacturers need to connect
patients with wrap-around services
that will help drive utilization and
support compliance, particularly when
medications are targeted toward small
patient populations. And, because
many of these treatments are
approved with a Risk Evaluation and
Mitigation Strategy (REMS),
manufacturers are required to
maintain patient registries, collect
data on patients who experience
adverse events, and report that data
back to FDA. These requirements vary
by therapy—in some cases
manufacturers may need to collect
patient data for as long as 10 years
after treatment. Successful
commercialization plans support
patients in improving compliance and
managing side effects, while also
collecting the related REMS data.
XV. THE VALUE OF Anticancer Drugs Market research
MARKETING report gives an expert, knowledgeable
RESEARCH and in-depth study of the major
Anticancer Drugs Market leading
players along with the company
profiles and strategies adopted by
them. this enables the buyer to gain a
telescopic view of the competitive
landscape and design the strategies
accordingly. A separate section with
Anticancer Drugs industry key players
is included within the report, which
provides a comprehensive analysis of
CAGR, value, cost, gross, revenue,
product picture, specifications,
company profile, and contact info.