Intro to Drugs, Dosage forms and Drug & Delivery systems

Drug

An agent intended for use in the diagnosis, mitigation, treatment, cure,
or prevention of disease in humans or in other animals (Food, Drug, and
Cosmetic Act, 1938)

Excipients

Inactive ingredients used in the preparation of dosage forms

Formulation

Pharmaceutical formulation, is the process in which different
chemical substances, including the active drug, are combined to produce a
final medicinal (drug) product

Drug product

A specific combination of an active pharmaceutical ingredient,
and generally, but not necessarily other inactive ingredients.

Dosage form:

Drug products in the form in which they are marketed for use
(tablets, capsules, solutions), with a specific combination of active ingredients
and inactive components (excipients), in a particular configuration

Drug substance (Active Pharmaceutical Ingredient)

It is the material that exerts the
pharmacological action. Along with other ingredients (excipients, inactives), it is
subsequently used to formulate the drug product

Impurity:

An impurity is any component present in the excipient, drug substance, or drug
product that is NOT:
• The desired product
• A product-related substance
• Or excipient, (including buffer components)

Prescription Drug:

A human drug that is not safe for use except under the supervision of
licensed medical practitioner

Drug Standards

• Uniform standards to ensure quality
• Development/publication of monographs and reference books
• Organized sets of monographs/books of standards – pharmacopeias or formularies

United States Pharmacopeia (USP)

Public organization, established in 1820

National Formulary (NF)

Initially developed to include drugs omitted by USP, merged with USP in 1975

Gene or Genome Sequencing

Building a library of gene/protein (genome/proteome) sequences to mine for information.

Target Discovery

• Look for proteins or mRNA expressed (or not expressed) in a disease.
• Look for genes/proteins essential for infectious agent and distinct from host genes/proteins.
• Look for genes and gene modifications associated with a disease.
• Look for proteins or protein modifications associated with a disease.
• Find regulatory pathways required for disease process.

Lead Discovery (Drug Discovery)

Discover leads (drug molecules) that affect the target gene, protein or pathway
• Inhibits a protein causing the disease.
• Activates a required protein.
• Inhibits the expression of a protein/pathway that causes the disease.
• Activates the expression of required protein/pathway.
• Stimulates protein modifications or cellular location

Drug Discovery Methods

1. Screening natural compound collections

2. Screening corporate compound collections
3. In silico screening

4. Rational Drug Design – HIV Protease

5. Combinatorial chemistry

Natural Compound Library Screening

• Random screening
• Testing compounds of natural origin for biologic activity
• Uses in vitro cell culture models or enzyme systems for testing

In silico screening

• Biological experiments conducted on a computer.
• 3D structure of a target (receptor, enzyme, protein etc.) used for screening.
• In silico tools simulate binding of candidate molecules to the target.
• Estimate the likelihood of successful interaction.

Gleevec

A tyrosine-kinase inhibitor used in the treatment of multiple
cancers, most notably Philadelphia chromosome-positive (Ph+)
chronic myelogenous leukemia (CML)

Rational Drug Design – HIV Protease

• Requires the knowledge of 3D structure of the target
• Specifically the active site
• Computer graphics used to design a drug with a specific structure that binds to the active site

Combinatorial Chemistry

▪ Preparation of a large number of different compounds at the same time.
▪ High throughput-screening provides the most promising substances.

Conventional reaction:

A + B → A-B

Combinatorial chemistry:

A(1-n) + B(1-n) -----→ A(1-n)-B(1-n)

Lead optimization

structure modifications to improve ADMET properties

ADMET: Ideal properties of drugs

• Absorption
• Distribution
• Metabolism
• Excretion
• Toxicity

Stages of drug development

Drug discovery → Animal studies → Clinical tests → Commercialization

Who is/are responsible for drug approval?

• A federal agency established in 1906 known as Food and Drugs Administration (FDA).
• Part of the Public Health Service (PHS), funded in part by Congress through the Department of Health and Human Services (HHS).
• Separate centers within the FDA regulate drugs, biologicals, devices, and food

Center for Biologics Evaluation and Research
(CBER)

approves biologics drugs.

Center for Drug Evaluation and Research (CDER)
approves small-molecule drugs.

Determines over-the-counter vs. prescription status.

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

To gain approval for marketing, a drug's sponsor (e.g., a pharmaceutical company) must
demonstrate, through supporting scientific evidence, that ______

• The new drug or drug product is safe and effective for its proposed use.

• 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

Pre-Clinical Phase

1. Biologic tests of toxicity and efficacy of therapy
   • Pharmacology
   • Drug metabolism
   • Toxicology

2. Preformulation studies

3. Formulation studies

Investigational New Drug (IND)

• Submit IND application
• FDA reviews all preclinical testing and plans for clinical testing to determine if the drug is safe to move to human trials
• FDA response time: 180 days

Phase I Clinical Trials

1. Low initial dose
2. Absorption and metabolism
3. Effects on organs and tissue
4. Side effects as dosage is increased

Approximately ____ of drugs may move to the next stage during clinical phase I trials

70%

Phase II Clinical Trials

1. Dose range
2. Effectiveness in treating disease
3. Short-term side effects

Approximately ____ of drugs may move to the next stage during clinical phase II trials

33%

Phase III Clinical Trials

1. Benefit/risk relationship of drug
2. Less common and longer-term side effects
3. Labeling information

Approximately ____ of drugs may move to the next stage during clinical phase III trials

25-30%

New Drug Application (NDA)

• File NDA, if clinical trials demonstrate the drug safety, and therapeutic effectiveness.
• Purpose is to gain permission to market the drug product in the united states.
• FDA must respond within 180 days of receipt of an application (known as review clock).
• Review clock can be extended.

Phase IV – Post marketing surveillance

• May contribute to the understanding of the drug's mechanism or scope of action.
• May indicate possible new therapeutic uses for the drug, and/or may demonstrate the
need for additional dosage strengths, dosage forms, or routes of administration.
• These studies may also reveal additional side effects, serious and unexpected adverse
effects, and/or drug interactions

Stages of Dosage Form Development

Reformulation, Formulation, Product stability and degradation kinetics

Preformulation

• Physicochemical properties
• Nature of drug
• Frame work

Formulation

• Tablets, Capsules
• Injections, Transdermal patches etc.

Product stability & degradation kinetics

• Shelf life

gene/genome sequencing

understand the disease

target discovery

identify the root cause of the disease, find disease target(s)