INTRODUCTION TO PHARM’L

DOSAGE FORMS AND DRUG

DELIVERY SYSTEMS
 Objectives:
1. Comprehension of drug, medicine, pharmacy;
2. Describe the process of drug discovery and development;
3. Discuss current good manufacturing practices and current good compounding
practices;
4. Describe drug delivery systems.
 DRUG
• Articles recognized in the official USP, NF
• Articles intended for use in the diagnosis, cure, mitigation, treatment, prevention
of disease in man and animals
• Articles (other than food) intended to affect the structure or any function of
body of man/animals
DRUG
• Articles intended for use as a component of any article specified in
the first 3 but does not include devices, or their components, parts or
accessories
• Active ingredient exerting therapeutic effect
MEDICINE
• Drug as the active ingredient + excipients formulated into a suitable
dosage form with complete packaging
• refers to a drug in their appropriate dosage forms, with assured
quality, safety and efficacy for animals or humans or both.
 PHARMACY
• the art, practice, or profession of preparing, preserving, compounding, and
dispensing medical drugs
• a place where medicines are compounded or dispensed
• also known as “apothecary” or “drugstore”
Drug discovery and development
Introduction
• The federal Food, Drug and Cosmetic Act, as regulated through Title
21 of the U.S> Code of Federal Regulations, requires a new drug to be
approved by the Food and Drug Administration (FDA) before it may
be legally introduced in the interstate commerce.
Sponsor’s goal:
✓To gain approval for its new product to be legally
available in the market.
How?
✓Demonstrate, through scientific evidence, that the
new drug or drug product is safe and effective for
its proposed use.
✓Must also demonstrate that the various processes and controls used
in producing the drug substance and in manufacturing, packaging,
and labeling are properly controlled and validated to ensure that the
product meets the established standards of quality.
✓The final labeling accurately represents the necessary information
for its proper use.
❑Some products, however have been approved and later removed
from the market for safety reasons.
 DRUG Drug Discovery & Development-
DISCOVERY Timeline
PRECLINICAL

CLINICAL TRIALS FDA

10,000 250 REVIEW 1 FDA
COMPOUNDS COMPOUNDS APPROVED
5 COMPOUNDS
DRUG

~6.5 YEARS ~7 YEARS ~1.5 YEARS

FDA approved drug indicates that:
✓Body of scientific evidence submitted sufficiently demonstrates that
the drug or drug product is safe and effective for the proposed
clinical indications;
✓There is adequate assurance of its proper manufacture and control
Drug Applications
IND (Investigational New Drug Application)
➢The sponsor of a new drug is required to file with the FDA an IND
before the drug may be given to human subjects.
Drug Applications
➢This is to protect the rights and safety of the subjects and to ensure
that the investigational plan is sound and is designed to achieve the
stated objectives.
➢The sponsor of an IND takes responsibility for and initiates a clinical
investigation.
Drug Applications
➢The sponsor may be an individual, pharmaceutical company,
governmental agency, academic institution, or some other private or
public organization.
Drug Applications
Treatment IND
➢A treatment IND or a treatment protocol
permits the use of an investigational drug in the
treatment of patients not enrolled in the clinical
study but who have a serious or immediately
life-threatening disease for which there is no
satisfactory alternative therapy.
Drug Applications
▪ The objective is to make promising new drugs available to
desperately ill patients as early as possible in the drug development
process.
• Conditions such as: adv cases of AIDS, herpes simplex
encephalitis, adv. Metastatic refractory cancers, bacterial
endocarditis, Alzheimer’s disease and others
Drug Applications
NDA (New Drug Application)
➢The purpose of NDA is to gain permission to
market the drug product in the Unites States.
➢An NDA contains a complete presentation of all of
the preclinical and clinical results that the sponsor
has obtained during the investigation of the drug.
Drug Applications
IND for orphan drug
▪ Orphan drug is used to treat a rare disease or condition thus called
also as orphan disease.
▪ Rare means only a few of the total population suffers from such
condition.
Drug Applications
Examples of Orphan disease/condition
Chronic lymphocytic leukemia, Gaucher disease, cystic fibrosis,
tourette syndrome, conditions related to AIDS
• adequate drugs for many of such diseases and
conditions have not been developed;
• because so few individuals are affected by any one rare
disease or condition, a pharmaceutical company which
develops an orphan drug may reasonably expect the
drug to generate relatively small sales in comparison to
the cost of developing the drug and consequently to
incur a financial loss;
▪ there is reason to believe that some promising orphan drugs will not
be developed unless changes are made in the applicable Federal laws
to reduce the costs of developing such drugs and to provide financial
incentives to develop such drugs; and
▪ it is in the public interest to provide such changes and incentives for
the development of orphan drugs.
www.fda.gov.com
 Other Drug Applications
SNDA- supplemental new drug application
ANDA-abbreviated new drug application, the
sponsor of the duplicate drug must provide
documentation on the chemistry, manufacturing,
controls and bioavailability of the proposed
product to demonstrate biologic equivalency to
the original product.
-But clinical data on the drug’s safety and efficacy are not required
because clinical studies were provided by the pioneer sponsor.
BLA (Biologics License Application)
-for the manufacture of bilogics such as blood products, vaccines, and
toxins
Animal Drug Applications
Medical Devices
Drug Discovery Methods
• Random Screening
• Molecular Manipulation
• Molecular Designing
• Drug Metabolites
• Serendipity
 Target Lead Medicinal In Vitro In Vivo Clinical Trials
Selection Discovery Chemistry Studies Studies and
Therapeutics
• Cellular and • Synthesis and • Library • Drug Affinity • Animal
Genetic Targets Isolation Development and models of
Selectivity Disease
• Genomics States
• Combinatorial • SAR Studies • Cell Disease
Chemistry • Behavioural
Models Studies
• Proteomics
• Assay • In Silico
development Screening • MOA • Functional
Imaging
• Bioinformatics
• High- • Chemical • Lead
Throughput Synthesis Candidate • Ex-Vivo
Screening Refinement Studies
 Target Selection
• Target selection in drug discovery is defined as the
decision to focus on finding an agent with a particular
Cellular &
Genetic Targets biological action that is anticipated to have therapeutic
utility — is influenced by a complex balance of scientific,
medical and strategic considerations.
Genomics
• Target identification: to identify molecular targets that
are involved in disease progression.
Proteomics • Target validation: to prove that manipulating the
molecular target can provide therapeutic benefit for
patients.
Bioinformatics

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Target Selection
Biochemical Classes of Drug Targets
➢ G-protein coupled receptors - 45%
Cellular &
Genetic Targets ➢ enzymes - 28%
➢ hormones and factors - 11%
Genomics ➢ ion channels - 5%
➢ nuclear receptors - 2%
Proteomics
Techniques for Target Identification
Bioinformatics

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Cellular & Genetic Targets:
Involves the identification of the function of a potential therapeutic drug
target and its role in the disease process.
Cellular &
Genetic Targets
For small-molecule drugs, this step in the process involves identification
of the target receptors or enzymes whereas for some biologic
Genomics approaches the focus is at the gene or transcription level.

Proteomics Drugs usually act on either cellular or genetic chemicals in the body,
known as targets, which are believed to be associated with disease.

Bioinformatics

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Cellular & Genetic Targets:
Scientists use a variety of techniques to identify and
Cellular & isolate individual targets to learn more about their
Genetic Targets functions and how they influence disease.
Genomics
Compounds are then identified that have various
Proteomics
interactions with the drug targets that might be
helpful in treatment of a specific disease.
Bioinformatics

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Genomics:
The study of genes and their function. Genomics aims to
understand the structure of the genome, including the mapping
Cellular & genes and sequencing the DNA.
Genetic Targets
Seeks to exploit the findings from the sequencing of the human
Genomics and other genomes to find new drug targets.

Proteomics Human Genome consists of a sequence of around 3 billion

nucleotides (the A C G T bases) which in turn probably encode
35,000 – 50,000 genes.
Bioinformatics

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Genomics:
Drew’s estimates that the number of genes implicated in disease,
both those due to defects in single genes and those arising from
Cellular & combinations of genes, is about 1,000
Genetic Targets
Based on 5 or 10 linked proteins per gene, he proposes that the
Genomics number of potential drug targets may lie between 5,000 and
10,000.

Proteomics
Single Nucleotide Polymorphism (SNP) libraries: are used to
compare the genomes from both healthy and sick people and to
Bioinformatics identify where their genomes vary.

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Proteomics:
It is the study of the proteome, the complete set of proteins
produced by a species, using the technologies of large – scale protein
Cellular & separation and identification.
Genetic Targets
It is becoming increasingly evident that the complexity of biological
systems lies at the level of the proteins, and that genomics alone will
Genomics not suffice to understand these systems.
It is also at the protein level that disease processes become manifest,
Proteomics and at which most (91%) drugs act.
Therefore, the analysis of proteins (including protein-protein, protein-
Bioinformatics nucleic acid, and protein ligand interactions) will be utmost importance
to target discovery.

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Proteomics:
Proteomics is the systematic high-throughput separation
and characterization of proteins within biological systems.
Cellular &
Genetic Targets
Target identification with proteomics is performed by
comparing the protein expression levels in normal and
Genomics diseased tissues.

Proteomics
2D PAGE is used to separate the proteins, which are
subsequently identified and fully characterized with LC-
MS/MS.
Bioinformatics

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Bioinformatics:
Bioinformatics is a branch of molecular biology that involves extensive analysis of
biological data using computers, for the purpose of enhancing biological research.
Cellular &
Genetic Targets
It plays a key role in various stages of the drug discovery process including
Genomics ➢ target identification
➢ computer screening of chemical compounds and
Proteomics ➢ pharmacogenomics

Bioinformatics

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Bioinformatics:
Bioinformatics methods are used to transform the raw sequence
into meaningful information (eg. genes and their encoded
Cellular & proteins) and to compare whole genomes (disease vs. not).
Genetic Targets
Can compare the entire genome of pathogenic and non-
Genomics pathogenic strains of a microbe and identify genes/proteins
associated with pathogenism

Proteomics Using gene expression micro arrays and gene chip technologies, a
single device can be used to evaluate and compare the
expression of up to 20000 genes of healthy and diseased
Bioinformatics individuals at once

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Lead Discovery:
• Identification of small molecule modulators of
Synthesis and
Isolation protein function
Combinatorial
• The process of transforming these into high-
Chemistry content lead series.
Assay
Development

High
Throughput
Screening

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Synthesis and Isolation:
• Separation of mixture
Synthesis and
Isolation • Separation of impurities
Combinatorial • In vitro chemical synthesis
Chemistry
• Biosynthetic intermediate
Assay
Development

High
Throughput
Screening

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Combinatorial Chemistry:
Rapid synthesis of or computer simulation of
Synthesis and large no. of different but structurally related
Isolation
molecules
Combinatorial
Chemistry • Search new leads
Assay
• Optimization of target affinity & selectivity.
Development • ADME properties
High
Throughput • Reduce toxicity and eliminate side effects
Screening

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Assay Development
• Used for measuring the activity of a drug.
Synthesis and
Isolation • Discriminate between compounds.
Combinatorial • Evaluate:
Chemistry
• Expressed protein targets.
Assay
Development • Enzyme/ substrate interactions.
High
Throughput
Screening

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 High throughput screening (HTS):
• Screening of drug target against selection of
Synthesis and
Isolation chemicals.
Combinatorial
• Identification of highly target specific
Chemistry compounds.
Assay
Development

High
Throughput
Screening

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 High throughput screening:

Synthesis and
Isolation

Combinatorial
Chemistry

Assay
Development

High
Throughput
Screening

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Medicinal Chemistry:
• It’s a discipline at the intersection of synthetic
Library organic chemistry and pharmacology.
Development
• Focuses on small organic molecules (and not
SAR Studies
on biologics and inorganic compounds)
• Used in
In Silico
Screening
• Drug discovery (hits)
• Lead optimization (hit to lead)
Chemical
Synthesis • Process chemistry and development
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 Library Development:
• Collection of stored chemicals along with
Library
Development associated database.
• Assists in High Throughput Screening
SAR Studies
• Helps in screening of drug target (hit)
In Silico
Screening • Based on organic chemistry
Chemical
Synthesis

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Structure-Activity Relationship (SAR)
Studies
• Helps identify pharmacophore
Library
Development • The pharmacophore is the precise section of
the molecule that is responsible for biological
SAR Studies activity
In Silico
• Enables to prepare more active compound
Screening • Allow elimination of excessive functionality
Chemical
Synthesis

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Structure-Activity Relationship (SAR)
Studies:

Library
Development

SAR Studies
Morphine Molecule
In Silico
Screening

Chemical
Synthesis

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 In silico screening:
• Computer simulated screening of chemicals
Library
Development • Helps in finding structures that are most likely
to bind to drug target.
SAR Studies
• Filter enormous Chemical space
In Silico
Screening • Economic than HTS
Chemical
Synthesis

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Chemical Synthesis:
• Involve production of lead compound in
Library
Development suitable quantity and quality to allow large
scale animal and eventual, extensive human
SAR Studies
clinical trials
In Silico • Optimization of chemical route for bulk
Screening
industrial production.
Chemical
Synthesis • Suitable drug formulation
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 In Vitro Studies:
• (In glass) studies using component of organism i.e. test tube
Drug Affinity experiments
and Selectivity • Examples-
Cell Disease • Cells derived from multicellular organisms
Models • Subcellular components (Ribosomes, mitochondria)
• Cellular/ subcellular extracts (wheat germ, reticulocyte
MOA
extract)
• Purified molecules (DNA,RNA)
Lead Candidate
Refinement

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 In Vitro Studies:
Advantages:
Drug Affinity • Studies can be completed in short period of time.
and Selectivity
• Reduces risk in post clinical trials
Cell Disease • permits an enormous level of simplification of the system
Models
• investigator can focus on a small number of components
MOA

Lead Candidate
Refinement

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Drug affinity and selectivity
• Drug affinity is the ability of drug to bind to its biological
Drug Affinity target (receptor, enzyme, transport system, etc.)
and Selectivity

Cell Disease • Selectivity- Drug should bind to specific receptor site on the
Models cell (eg. Aspirin)

MOA

Lead Candidate
Refinement

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Cell disease models
• Isogenic human disease models- are a family of cells that are
Drug Affinity selected or engineered to accurately model the genetics of a specific
and Selectivity patient population, in vitro

Cell Disease
Models • Stem cell disease models-Adult or embryonic stem cells carrying
or induced to carry defective genes can be investigated in vitro to
understand latent molecular mechanisms and disease characteristics
MOA

Lead Candidate
Refinement

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Lead Candidate refinement
• Optimizing chemical hits for clinical trial is commonly referred
Drug Affinity to as lead optimization
and Selectivity • The refinement in structure is necessary in order to improve
Cell Disease • Potency
Models • Oral Availability
• Selectivity
MOA
• pharmacokinetic properties
Lead Candidate • safety (ADME properties)
Refinement

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 In vivo studies
• Its experimentation using a whole, living
Animal models of
Disease States
organism.
• Gives information about,
Behavioural
Studies
• Metabolic profile
Functional
Imaging
• Toxicology
• Drug interaction
Ex-Vivo Studies

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Animal models of disease states
• Test conditions involving induced disease or
Animal models of injury similar to human conditions.
Disease States
• Must be equivalent in mechanism of cause.
Behavioural
Studies
• Can predict human toxicity in 71% of the
cases.
Functional
Imaging
• Eg. SCID mice-HIV
NOD mice- Diabetes
Ex-Vivo Studies Danio rerio- Gene function
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 Behavioural Studies
• Tools to investigate behavioural results of drugs.
Animal models of
Disease States
• Used to observe depression and mental disorders.
• However self esteem and suicidality are hard to induce.
Behavioural
Studies • Example:
• Despair based- Forced swimming/ Tail suspension
Functional
Imaging • Reward based
• Anxiety Based
Ex-Vivo Studies

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Functional Imaging:
• Method of detecting or measuring changes in
Animal models of
Disease States
metabolism, blood flow, regional chemical
composition, and absorption.
Behavioural
Studies • Tracers or probes used.
Functional
• Modalities Used-
Imaging • MRI
Ex-Vivo Studies • CT-Scan

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Ex-Vivo Studies:
• Experimentation on tissue in an artificial
Animal models of
Disease States
environment outside the organism with the
minimum alteration of natural conditions.
Behavioural
Studies • Counters ethical issues.
Functional
• Examples:
Imaging • Measurement of tissue properties
Ex-Vivo Studies • Realistic models for surgery

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Clinical trials:
• Set of procedures in medical research and
Phase-I drug development to study the safety and
efficacy of new drug.
Phase-II
• Essential to get marketing approval from
Phase-III
regulatory authorities.
• May require upto 7 years.
Phase-IV

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Phase 0:
• Recent designation, also known as human micro-dosing
studies.
Phase-I • First in human trials, conducted to study exploratory
investigational new drug.
Phase-II • Designed to to speed up the development of promising
drugs.
• Concerned with-
Phase-III
• Preliminary data on the drug’s pharmacodynamics
and pharmacokinetics
Phase-IV • Efficacy of pre-clinical studies.

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Phase I:
• Clinical Pharmacologic Evaluation
Phase-I • First stage of testing in human subjects.
• 20-50 Healthy Volunteers
Phase-II
• Concerned With:
Phase-III – Human Toxicity.
– Tolerated Dosage Range
Phase-IV
– Pharma-cology/dynamics
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 Phase I:
Types of Phase-I Trials
Phase-I • SAD (Single Ascending Dose)
• MAD (Multiple Ascending Dose)
Phase-II
• Food effect
Phase-III

Phase-IV

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Phase II:
• Controlled Clinical Evaluation.
Phase-I • 50-300 Patients
• Controlled Single Blind Technique
Phase-II • Concerned With:
– Safety
Phase-III – Efficacy
– Drug Toxicity
Phase-IV – Drug Interaction
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 Phase III:
• Extended Clinical Trials.
Phase-I • Most expensive & time consuming.
• 250-1000 Patients.
Phase-II • Controlled Double Blind Technique.
• Concerned With:
Phase-III – Safety, Efficacy
– Comparison with other Drugs
Phase-IV – Package Insert
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 Phase IV:
• Post Marketing Surveillance.
Phase-I • Designed to detect any rare or long-term
adverse effects.
Phase-II • Adverse Drug Reaction Monitoring.
• Pharmacovigilance.
Phase-III

Phase-IV

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Gene Therapy
• Technique for correcting defective genes.
• It is the process of inserting genes into cells to
treat diseases.
• Gene therapy is used to correct a deficient
phenotype.
 Gene-therapy approaches
Germline Gene Therapy
➢Sperm or eggs, are modified by the introduction of functional genes, which are
integrated into their genomes.

➢Change would be heritable and would be passed on to later generations.

Somatic Gene Therapy

➢The therapeutic genes are transferred
Into the somatic cells of a patient.

➢Change will not be inherited by the

patient's offspring or later generations.
Gene Therapy- Types
Ex Vivo Gene Therapy
➢Transfer of therapeutic genes in cultured cells which are then reintroduced into
patient.

Eg: Therapy for ADA Deficiency

In Vivo Gene Therapy

➢The direct delivery of genes into the cells of a particular tissue is referred to as in
vivo gene therapy.

Eg: Therapy for Cystic fibrosis

Gene Therapy-Vectors
• Viruses
Retroviruses
Adenoviruses
Adeno-associated viruses
Herpes Simplex viruses
• Pure DNA Constructs
• Lipoplexes
• DNA Molecular Conjugates
• Human Artificial Chromosome
Gene Therapy Limitations
• Short lived nature of gene therapy
• Immune response
• Problems with viral vectors
• Multigene disorders
Recent Developments
• Nanotechnology + gene therapy yielded treatment to
torpedo cancer
• Results of world's first gene therapy for inherited
blindness show sight improvement
• New Method of Gene Therapy Alters Immune Cells for
Treatment of Advanced Melanoma
• Dual Gene Therapy Suppresses Lung Cancer in
Preclinical Test