Drug Delivery Systems Module 1

IND for patients with life-threatening or severely debilitating ilnesses, where no satisfactory alternative exists

Expanded Access ("compassionate use") IND

The type of membrane passage where the drug diffuses down its concentraion gradient without the aid of a transporter

Passive Diffusion

IND filed during Phase 1 or 2 to allow treatment of the desperately ill before full FDA approval

Treament Protocol for Compassionate Use

Orphan Disease

a rare disease or condition that affects fewer than 200,000 patients in the United States

The type of NDA for changes in labeling, method of synthesis, formulation, analytical standards, container, manufacturing facilities, and adding a new indication

Supplemental New Drug Appliction (SNDA)

A measure of a drug's concentration in a non-polar organic phase to that in a polar aqueous phase

Partition Coefficient

First-Pass Metabolism definition

Drug metabolism that occurs before reaching the systemic circulation

How does blood perfusion affect distribution of a drug in the body?

Drugs distribute faster to well-perfused organs (liver, kidney, brain), drugs distribute slower to less-perfused organs (muscle, fat, skin)

What benefits exist for drug manufacturers developing drugs for orphan diseases?

Tax incentives, financial support for clinical trials, and 7 year exclusivity

The movement of molecules of solutes or solvents from one region to another

Mass Transport

The type of NDA for generic drug products

Abbreviated New Drug Application (ANDA)

How should a drug be administered if you want the drug to be directly administered into the circulation?

Intravascularly (intravenous (IV) is most common)

ABC Transporters definition

Active transporters that utilize ATP for their energy

The type of drug transport where drug is transported across a membrane against its concentration gradient

Active Transport

Diffusion across a membrane down its concentration with the help of a transporter protein

Facilitated Diffusion

Which expedited program allows drug approval based on a surrogate endpoint?

Accelerated Approval

Where can drug targets be found?

Throughout the body (organs, tissues, cells)

What does LADME stand for?

Liberation

Absorption

Distribution

Metabolism

Excretion

Xenobiotic definition

Foreign chemicals, including drugs

The two primary locations where first-pass metabolism may occur following oral drug administration?

1) Enterocytes

2) Hepatocytes

In terms of protein binding, a drug must be in what form to leave the vasculature?

Free (unbound)

As a requirement for generic drug approval [...] means no clinically significant difference in bioavailability.

bioequivalent

What is the purpose of Phase 2 clinical trials?

Mainly effectiveness, but also short-term safety

What is the purpose of Phase 3 clinical trials?

Confirm effectiveness and longer-term safety

The NDA phase that occurs after the drug is approved by the FDA

Phase 4 / post-marketing surveillance

What is the patient population used for Phase 1 clinical trials?

Usually healthy volunteers

What is the purpose of Phase 1 clinical trials?

Determine safety and dosage

What patient population is used in Phase 2 clinical trials?

Patients suffering from the indicated condition

What patient population is used in Phase 3 clinical trials?

In patients suffering from the indicated condition (more patients than Phase 2 trials)

Reasons bioavailability is typically less than 100% for extravascular routes?

1) Incomplete dissolution

2) Incomplete absorption through epithelia

3) Bypassing absorptive area

4) Pre-systemic metabolism (first-pass metabolism)

5) Chemical degradation

Where in the body does drug typically have the most difficulty passing into the interstitial fluid?

Central Nervous System (CNS) - efflux transporters and tight junctions between endothelial cells restrict the easy passage of drugs

What 4 FDA programs exist fo expedite development and review of drugs to address an unmet medical need?

1) Fast Track

2) Breakthrough Therapy

3) Accelerated Approval

4) Priority Review

3 major processes involved in renal drug excretion

1) Glomerular filtration

2) Secretion

3) Reabsorption

As a requirement for generic drug approval, therapeutically equivalent means [...] + [...]

pharmaceutically equivalent + bioequivalent

Are nonpolar or polar drugs more likely to be reabsorbed back into the bloodstream in the kidney?

Non-polar drugs are more likely to be reabsorbed (by passive diffusion)

Liberation

Release of the drug from its dosage form

Why is lipid solubility important to consider for membrane passage?

In most cases, drug must have enough lipophilicity to pass through lipid biayer membranes.

On average, how long does it take to get a response on an NDA with a Priority Review?

6 months

Crystal Habit definition

Description of the outer appearance of a crystal

On average, how long does it take to get a response on an NDA without a Priority Review?

10 months

What determines the crystal habit?

Internal structure of the crystal

What must happen immediately after liberation in order for a drug to act on a target?

Go into solution (unless it is already dissolved)

Amorphous form definition

No repeating (periodic) arrangement

What is a target in drug discovery?

Molecule or stucture that is linked to a particular disease

Hygroscopicity definition

The tendency of a substance to take up atmospheric moisture

Prior to FDA approval, drug manufacturing facilities will be inspected to ensure they are in compliance with what?

FDA's Current Good Manufacturing Practices

Polymorphism definition

Capacity for appearing in many forms (drugs may exist in different molecular arrangements)

What must be filed with the FDA after clinical trials before a drug can be considered for approval?

New Drug Application (NDA)

Metastable definition

being in an unstable and transient but relatevely long-lived state of a chemical or physical system (may change over time to a more stable form)

The expedited program for a serious condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s)

Breakthrough therapy

Solvate definition

A crystal containing solvent molecules within the crystal latticee.g., a hydrate

The FDA defines this as "the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action"

Bioavailability

The compounding pharmacy you are working in has run out of a patient's normal anhydrous form of a drug and instead compounds the oral medication with the dihydrate form. Why is this not acceptable?

Hydrates are typically less soluble than their anhydrous counterparts (not interchangeable)

What is the candidate in drug discovery?

The lead that is the most suitable for further investigation.

Stratification definition

Process of arranging in layers

What is a hit in drug discovery?

A molecule that interacts with targets

Solution definition

A homogeneous mixture of two or more substances

The letter a pharmaceutical company receives from the FDA indicating that the application is not ready for approval

Complete response letter

Solubility definition

The concentration of a solute in a saturated solution at a certain temperature (amount dissolved per volume)

The specific [FDA approved] use for a drug, i.e. its "labeled" use

indication

Why are amorphous solids and metastable crystals more soluble than their more stable counterparts?

Looser molecular arrangement

ADME properties depend largely on what properties of the drug?

Physiochemical properties

The pH at which a drug is 50% ionized

pKa

The type of NDA review where the time of review is reduced from 10 months to 6 months

Priority review

99.9% of drug will be fully ionized at?

Bases: at 3 pH units below pKa

Acids: at 3 pH units above pKa

What is the lead in drug discovery?

A prototype chemical that has the desired biological or pharmacological activity.

Most prodrugs are created with what linkage?

Ester linkage

How long must a disease last to be considered a chronic disease?

3 months or longer

A synthetic derivative of a drug that is transformed in vivo to liberate an active drug molecule

Prodrug

What application must be submitted to the FDA prior to beginning clinical studies?

Investigational New Drug Application (IND)

As a requirement for generic drug approval [...] means identical API, strength, dosage form, and route (though excipents can be different)

pharmaceutically equivalent

In the accelerated approval pathway, a marker thought to predict clinical benefit

surrogate endpoint

ADME Studies

Absorption, Distribution, Metabolism, Excretion

Static or Stagnant Boundary Layer

A highly concentrated solute layer around a dissolving solid when solute movement is stagnant relative to movement in the bulk liquid

Noyes-Whitney equation describes what?

The dissolution rate of a solid in a liquid

How are the size of a solid particle and the exposed surface area related?

Inversely

For a given mass of particles, as the particle size decreases, the exposed surface area increases

Thickness of the static boundary layer can be decreased by what?

Agitation

The movement of a molecule from one phase into another phase (e.g., between polar and nonpolar phases)

Partition

Will the unionized form of a drug likely have a smaller P or larger P than the ionized form?

Larger

Unionized --> less polar --> more lipophilic --> larger P

What are the two main purposes of using a buffer?

Adjusting the pH to optimize a drug's solubility and/or stability

Cosolvents definition

Solvents used in combination to increase a solute's solubility ("like dissolves like")

In practice, cosolvents are usually blended with what to achieve optimal polarity?

Water

These amphiphilic molecules that have a tendency to accumulate (adsorb) at the interface between 2 phases

Surfactants

Amphoteric definition

Having an acidic and basic moiety

Amphiphillic definition

Having an affinity for both polar and nonpolar substances

Micelle definition

Aggregate formed from the self-association of surfactant monomers

Critical Micelle Concentration definition

The concentration of surfactant at which sufactant molecules will self-associate to form micelles

How do micelles help solubilize drugs?

Nonpolar drugs: dissolve within lipophilic pool within hydrocarbon core

Amphiphilic drugs: will intersperse among the surfactants

Cyclodextrin solubilize by "hosting" lipophilic compounds (e.g., drugs) in their hydrophobic core

"guest"

What functional group at the entrance of cyclodextrins is responsible for interacting with water?

Hydroxyl (-OH)

What type of interaction allows poorly soluble drugs to fit within the hydrophobic core of a cyclodextrin?

Noncovalent interaction

"the extent to which a drug product retains, within specified limits, and throughout its period of storage and use (shelf-life), the same properties and characteristics that it possessed at the time of its manufacture"

Drug stability

organoleptic properties

susceptible to sensory impressions (ex. smell, color, taste)

hydrolysis definition

cleavage of a molecule by reaction with water

functional groups that make a drug susceptible to hydrolytic cleavage

esters, amides, lactams, lactones

autoxidation definition

a type of oxidation tha involves the uncatalyzed oxidation of a substrate by molecular oxygen (slow)

superoxide, hydrogen peroxide, hydroxyl radical are examples of:

Reactive oxygen species (ROS)

Steps of free radical oxidation:

1. initiation 2. propagation 3. termination

propagation of free radicals

free radicals grow in number

In the termination stage of the free radical mechanims of oxidation, free radicals...

combine to form chemically inert products