Drug Delivery Systems - Exam #1

List the steps in the Drug Development Cycle (6)

1. Discovery

2. Preclinical studies

3. IND application

4. Clinical trials

5. NDA application

6. Post-marketing surveillance

Time period of the Drug Discovery Process in the Drug Development Cycle

2-4+ years

Time period of the Preclinical Studies in the Drug Development Cycle

1-2+ years

What are some of the challenges in the Drug Development Process? (14)

-Potent

-Selective

-Reversible

-Targeted

-Soluble

-Long-lasting

-Metabolically stable

-Permeable

-Non-toxic

-Non-mutagenic

-Non-teratogenic

-Physically stable

-Patentable

-Manufacturable

What are the roles of The Food and Drug Administration? (3)

1. Regulates pharmaceutical market

2. Ensures human safety and efficacy

3. Has authority by Federal Food, Drug, and Cosmetic Act

Experts from what areas come together to form a drug discovery project team? (5)

1. Biology

2. Chemistry

3. ADME

4. Toxicology

5. Pharmaceutical Sciences

Target Identification

As disease biology becomes more understood, new potential drug intervention points are identified (receptors, enzymes, ion-channels, agonists, etc.)

Target Validation (2 points)

-Clinical Proof of Concept (POC) = Right Target + Right Drug

-Evaluate target and confirm its role in disease

What components are a part of the Preclinical Stage of the Drug Discovery Process? (4)

1. Basic material properties

2. In vitro cell testing

3. In vivo animal testing

4. ADME/Toxicity studies

Lead Optimization (2 points)

-Chemically related series that survive screening are optimized to improve their safety/efficacy

-Structure-Activity Relationship (SAR) with chemical structure of current drug

True or False. An IND application does not need to be approved before First-in-Human (FIH) clinical trials.

False

What is contained within an Investigational New Drug (IND) application? (3)

1. Acute toxicity of drug substance in at least 1 animal species

2. Short-term toxicity studies

3. Pharmacological profile of drug substance

Components of Phase I Clinical Trials (4)

-First-in-human dosing to healthy volunteers

-Administration of single escalating doses to a small number of subjects (10-15)

-Short-term multiple doses (~2 weeks)

-Assess safety & PK

Components of Phase II Clinical Trials (4)

-First dosing to patients (20-100 subjects)

-First evaluation of efficacy

-Safety profile & PK monitored

-Assess proof-of-concept

Components of Phase III Clinical Trials (3)

-Test effectiveness of drug for particular indications in patients

-Common effects documented in larger populations (>1000 subjects)

-Finalize prescribing label

Components of Phase IV Clinical Trials (2)

-Post-marketing approval studies

-Additional information about effectiveness and safety (300-3000 volunteers)

What is required for a New Drug Application (NDA)? (5)

1. Results from clinical trials

2. Results on safety/efficacy

3. Method of manufacture and quality control analysis

4. Proposed labeling details for product

5. Details on long-term studies and post-marketing surveillance

Brand name drug requirements for an NDA (8)

1. Chemistry

2. Manufacturing

3. Controls

4. Labeling

5. Testing

6. Animal studies

7. Clinical studies

8. Bioavailability

Generic drug requirements for an ANDA (6)

1. Chemistry

2. Manufacturing

3. Controls

4. Labeling

5. Testing

6. Bioequivalence

What aspects of an NDA can be omitted from for an ANDA? (3)

1. Animal studies

2. Clinical studies

3. Bioavailability

What does Cmax correspond to?

Effectiveness, safety

What does AUC correspond to?

Exposure, effectiveness, bioavailability

What does Tmax correspond to?

Absorption rate, input rate

What does t1/2 correspond to?

Elimination rate

What does ∂Ct/∂t stand for in the Noyes-Whitney equation?

dissolution rate

What does Cs stand for in the Noyes-Whitney equation?

solubility of drug

What does Ct stand for in the Noyes-Whitney equation?

drug concentration of bulk fluid

What does k stand for in the Noyes-Whitney equation?

dissolution rate constant

What does S stand for in the Noyes-Whitney equation?

surface area

What does Fick's First Law equation evaluate?

how efficiently drugs cross barriers

What is Fick's First Law equation (sink condition)?

J = DKC(0)/I

What is Fick's First Law equation (amount/time)?

∂m/∂t = ADKC(0)/I

Physiochemical properties influencing drug absorption (5)

1. Lipid solubility

2. pKa

3. MW and volume

4. Aqueous solubility

5. Chemical stability

What are the typical oral drug absorption routes? (3)

1. Transcellular pathway

2. Paracellular pathway

3. Transport via protein pump

Lipinski's Rule of 5

1. MW < 500 g/mol

2. logK < 5

3. <5 hydrogen bond donors

4. <10 hydrogen bond acceptors (N & O)

A _________ is a medication that is metabolized into a pharmacologically active drug

prodrug

Which BCS classifications (I, II, III, or IV) apply to the most difficult drugs to deliver orally?

Class II and IV

Class I of Biopharmaceutics Classification System (BCS)

High solubility, high permeability (ex. Metoprolol)

Class II of Biopharmaceutics Classification System (BCS)

Low solubility, high permeability (ex. Carbamazepine)

Class III of Biopharmaceutics Classification System (BCS)

High solubility, low permeability (ex. Atenolol)

Class IV of Biopharmaceutics Classification System (BCS)

Low solubility, low permeability (ex. Ritonavir)

Role of Excipients in Drug Products

Promote

-manufacturability

-stability

-bioavailability

-accurate dosing

-patient acceptance and convenience

What is a common measurement of drug potency?

EC50 (lower EC = higher potency)

Therapeutic Index (TI)

Degree of separation between toxic and therapeutic doses

Systemic controlled drug delivery routes (7)

1. Oral route

2. Intravenous route

3. IM or SC

4. Transdermal

5. Sublingual or buccal

6. Intranasal

7. Pulmonary

Dissolution

the process and rate at which a drug moves from the solid state into solution

What does the model called the "Hixon-Crowell Cube Root Law" take into consideration that other models don't consider?

Particle size shrinkage during dissolution

Which parameter is present in all dissolution mathematical models?

Solubility

Which dissolution technique would you use to select the most preferable salt or polymorph of an insoluble drug?

Intrinsic dissolution test

What biologic component(s) can be added to a dissolution medium to better simulate fed and fasted conditions in the intestinal tract?

Lecithin and sodium taurocholate

What effect can excessive lubricant have on drug absorption from tablets and capsules?

Decreased dissolution rate

How can the unstirred layer thickness surrounding a dissolving drug particle be reduced to increase the dissolution rate?

Increase the agitation rate

Dissolution rates are directly proportional to what? (3)

1. Drug diffusion coefficient

2. Surface area of exposed drug

3. Drug solubility

What are the three necessary qualities for successful tablet product development captured in the Product Development Triangle?

1. Stability

2. Manufacturability

3. Bioavailability

At what part of the intestinal tract is it most likely for a weakly basic drug to rapidly dissolve?

Stomach

Why is helpful to establish an in vitro/in vivo (IVIVC) correlation during development of a drug product? (3)

1. To help choose a manufacturing process

2. To help choose appropriate excipients

3. To assist with selecting storage conditions for shelf life determination

Why should we choose the oral route for medications? (3)

1. Most convenient form of administration

2. Most cost effective

3. Flexibility in dosage regimen

What is Surface Area (A) affected by? (3)

1. Particle size

2. Dispersibility of powdered solid

3. Porosity of solid particles

What is Saturated Solubility (Cs) affected by? (5)

1. Temperature

2. Nature of medium

3. Molecular structure of solute

4. Crystalline form of solid

5. Presence of other compounds

What is Concentration of Solute at time t (Ct) affected by? (2)

1. Volume of medium

2. Processes that removed dissolved solute from medium

What is the Dissolution Rate Constant (k) affected by? (2)

1. Diffusion coefficient D of solute

2. Viscosity of medium

What is Thickness of Boundary (h) affected by?

Degree of agitation

Generally, as A (surface area) increases, the dissolution rate will...

also increase

What component can be added to a formulation to overcome aggregation due to particle size?

Surfactants

The apparent thickness of the stagnant layer can be reduced when a drug dissolves into a ___________ medium (ex. weak base in an acidic medium)

reactive

Salts of weak acids and weak bases generally have a much _________ aqueous solubility than the free acid or base (ex. Penicillin V)

higher

What are the types of tablets?

Compressed and molded

Purpose of a diluent in a tablet

Increases bulk

What are the types of diluents used in tablets?

Organic and inorganic

What is the purpose of tablet binders?

work as binding agents to assist in granulation

What is the purpose of disintegrators in tablets?

cause the tablet to break apart into solution

What is the purpose of lubricants in tablets?

reduce friction and prevent sticking during production

What is the purpose of glidants in tablets?

improve the powder flow into the tableting machines for compaction

What are the two super disintegrants that can break up a tablet/capsule within 15 minutes?

croscarmellose sodium, sodium starch glycolate

Purpose of tablet coating (9)

1. Enhance palatability

2. Increase stability

3. Increase mechanical integrity

4. Enhance appearance

5. Avoid staining

6. Avoid side effects

7. Separate incompatible substances

8. Modify drug release profiles

9. Identifier

List the types of tablet coatings (5)

1. Sugar

2. Film

3. IR

4. Delayed release (enteric)

5. CR

What are the types of capsules?

hard gelatin and soft gelatin

Hard gelatin capsules are filled with... (4)

1. Solids (tablets)

2. Powders

3. Granular or pelletized materials

4. Oils

Soft gelatin capsules are filled with... (3)

1. Semisolids

2. Liquids

3. Granular or pelletized materials

Capsules sizes are identified by numbers. The sizes commonly used for human consumption are...

000, 00, 0, 1, 2, 3, 4, 5

Hard gelatin capsules containing hydrophobic drug particles should contain...

hydrophilic diluent particles

Alternate material to gelatin in capsules (2)

1. Pullulan, water soluble polysaccharide

2. HPMC, a water soluble polymer

Buccal - General location

Cheek

Sublingual - General location

Ventral tongue; floor of mouth

Gingival - General location

Gums surrounding teeth

Palatal - General location

"Roof" of mouth

Magnesium stearate - Role of Excipient

Lubricant

Corn starch - Role of Excipient

Disintegrant (also a diluent, binder)

Colloidal silicion dioxide - Role of Excipient

Glidant

Gelatin - Role of Excipient

Binder/diluent

Calcium stearate - Role of Excipient

Lubricant

Stearic Acid - Role of Excipient

Lubricant

Titanium Dioxide - Role of Excipient

Coloring agent

Sodium laurel sulfate - Role of Excipient

Lubricant

PVP or Povidone - Role of Excipient

Disintegrant

Propyl paraben - Role of Excipient

Preservative

Benzalkonium bromide - Role of Excipient

Preservative

Ferric oxide - Role of Excipient

Coloring agent

Controlled release definition

delivers a drug in a manner that is planned, predictable, and slower-than normal

What are the 4 types of controlled release systems

1. Sustained-release

2. Delayed-release

3. Targeted-release

4. Responsive-release