Oral Drug Delivery (3/13/26) - Pharmaceutics II

What are some advantages of Oral routes of administration?

Easy and Convenient

Easy Formulation

Economical

High Patient Compliance

What are some limitations (8) of Oral routes of administration?

Variable Absorption

Gastric Irritation may cause vomiting

Not useful if patient is vomiting

Requires cooperation of patient

Drugs are susceptible to harsh conditions in the GI Tract (acid / proteolytic enzyme)

Onset of effect is slow

Presence of food may affect the drug absorption

Pre-Systemic elimination in the liver

How do oral drug forms differ for Local and Systemic effects?

Give examples of each type.

Local Effects: drugs act directly in the GI tract without entering system bloodstream (very few drugs; usually Antacids and laxatives)

- Example: Maalox and Mylanta to supply OH and neutralize excess stomach acid production

Systemic Effects: drugs access sites of action through diffusion equilibrium between blood and extravascular tissues after absorption into the systemic bloodstream (oral is most frequent systemic route)

- Example: Analgesics (Tylenol) and Antimicrobials (Penicillin)

What are the two most critical factors that influence the delivery of a drug into the Systemic circulation?

1. Solubility - dissolution of solid particles to liquid molecules in GI contents

2. Permeability - diffusion of molecules from Small Intestine contents into membrane capillaries

How do we typically describe the structure of the Plasma Membrane?

What components comprise this Membrane?

How does this membrane serve its role?

Mosaic of Components

Components include:

- Phospholipids

- Cholesterol

- Proteins

- Carbohydrates

Movement of this 'mosaic' helps maintain the barrier between the inside and outside of the cell environments

What molecular properties increase diffusion of the drug across biological membranes?

Molecular Weight ideally less than 500, but can be less than 1000

Lipophilic preferred

- logP ranges from 2-5

Structure (charged species / ionized, nonelectrolytes / sugar)

How do large, charged, and water-soluble molecules cross the membrane?

Give an example.

Must use carrier or channel proteins to cross as they cannot just diffuse across

- Example: C6H12O6 and ions have to use these proteins

What is In Vitro?

In vivo?

Ex vivo?

In Vitro - performed / takes place in a test tube, culture dish, or elsewhere OUTSIDE a living organism

In Vivo - performed / takes place in a LIVING organism

Ex Vivo - experiments, tests, or procedures conducted on cells or organs removed from a living organism and maintained in an external, controlled environment

Describe In Vitro to In Vivo correlation.

1. In Vitro dosage --(dissolution)--> 2. In Vitro solution

(IVIVC LINK)

3. In Vivo Dosage --(dissolution)--> 4. In Vivo Solution --(absorption)--> 5. Blood Concentration --(elimination)-->

What is meant by IVIVC?

What is required by the USP for each solid oral dosage form?

IVIVC = In-Vitro dissolution profile can reliably predict the In-Vivo absorption profile

USP requires In Vitro Dissolution standards for each one

How do In Vitro Dissolution standards provided as required by the USP affect oral dosage forms?

Plasma Drug Conc. predicts clinical drug response more accurately

Drugs swallowed in a solid form must dissolve as molecules in GI contents before diffusion into blood capillaries in the SI Membrane or Wall

How does In Vitro dissolution correlate to predictable In Vivo absorption and, therefore, give a good IVIVC relationship?

If every batch dissolves in the same way in the lab, the drug will usually be absorbed in the same way in the body

This allows for a strong IVIVC to be built

What does BCS stand for?

Biopharmaceutical Classification System

What two parameters are used to categorize drugs according to the BCS?

Why were these two parameters chosen?

1. Solubility / Dissolution

2. Permeability / Diffusion

Chosen because most PO drugs are absorbed via Passive Diffusion through the SI, where extent of oral absorption is influenced by the drug's membrane PERMEABILITY and SOLUBILITY

Give each class under the BCS.

Be sure to indicate the parameters for each class.

Class I:

- HIGHLY permeable

- HIGHLY soluble

Class II:

- HIGHLY permeable

- POORLY soluble

Class III:

- POORLY permeable

- HIGHLY soluble

Class IV:

- POORLY permeable

- POORLY soluble

What types of compounds are usually included in BCS Class I?

How do In Vitro dissolution studies affect these compounds' expected performance?

Compounds that are normally expected to DISSOLVE QUICKLY in Gastric and Intestinal Fluids + readily cross the intestinal wall through passive diffusion

In Vitro dissolution studies are thought to provide sufficient information to assure In Vivo product performance (NO BIOEQUIVALENCE STUDIES NECESSARY)

What are the rate limiting steps for BCS Class II compounds?

How do we address these rate limiting steps?

Give examples.

Poor solubility and / or slow dissolution

Formulations are designed to overcome SOLUBILITY or DISSOLUTION RATE problems

Example:

- Salt Formation (naproxen sodium)

- Particle Size Reduction

- Lipid Based Formulations (doxil)

What are the rate limiting steps for BCS Class III compounds?

How do we address these rate limiting steps?

Give examples.

Passive Diffusion is the rate-limiting step

Most effective method is to INCREASE MEMBRANE PERMEABILITY (via prodrugs or permeation enhancers)

Example:

- L-Dopa / Levodopa (anti-Parkinsonism agent)

What is the difference between a Pro Drug and an Active Drug?

Pro Drug - drug is inactive before metabolism, then is activated after metabolism

Active Drug - drug takes effect directly, without needing activation

What two approaches do we use to increase membrane permeability for BCS Class III compounds?

1. Prodrugs

2. Permeation Enhancers

Why do we refer to BCS Class IV compounds as 'good for nothing'?

They exhibit POOR SOLUBILITY and POOR PERMEABILITY and pose tremendous challenges

They have no guarantee of success

Which BCS Class of compounds do not require Bioequivalence Studies?

BCS Class I

For each of the BCS Compound Classes, what are their relative IVIVC?

Class I:

- HIGH or BEST IVIVC

- good hydrophilic / lipophilic balance

Class II:

- LOW, but ADEQUATE IVIVC

- dissolution-dependent absorption

Class III:

- POOR IVIVC

- diffusion-dependent absorption

- rarely effective by mouth

Class IV:

- WORST or NO IVIVC

- ineffective by mouth

What key factors are considered for the BCS classification system?

Solubility, Permeability, and Dissolution

What is the major limitation of the BCS?

What was proposed in response to this limitation?

Does NOT provide an in-depth understanding of how drug METABOLISM and DRUG TRANSPORT may impact pharmacokinetic performance of drug products

Biopharmaceutical Drug Disposition Classification System (BDDCS) was proposed in response

What does the high permeability of BCS Class I and II compounds allow for?

How does this affect their elimination patterns?

Allows for ready access to metabolizing enzymes within hepatocytes

Therefore, they are eliminated primarily by METABOLISM

What type of permeability do BCS Class III and IV compounds have?

How does this affect their elimination patterns?

LOW permeability

They are primarily eliminated unchanged into the Urine and Bile

What two factors does BCS guidance consider?

What major factor does BDDCS guidance consider?

BCS:

- 1. Solubility / Dissolution

- 2. Permeability / Diffusion

BDDCS:

- 1. Metabolism

What are the seven steps in the Oral Drug Absorption Sequence?

1. API EXPOSURE - dissolution and disintegration of tablet coatings and capsule shells

2. DEAGGREGATION - of compacted powders

3. DISSOLUTION - of solid APIs into liquid molecules

4. DIFFUSION - API molecules from SI contents into membrane capillaries

5. BLOOD TRANSPORT - intestinal membrane vessels to hepatic portal vein, then portal vein to liver

6. LIVER EFFECTS - (a) possible first pass metabolism, (b) transport of drug + metabolites into hepatic vein, inferior vena cava, then systemic bloodstream

7. ABSORPTION - API or prodrug metabolite in systemic bloodstream

What happens during the API Exposure step of the Oral Drug Absorption Sequence?

Tablet disintegrates and the tablet coatings or capsule shells dissolve

What happens during the Deaggregation of the Oral Drug Absorption Sequence?

Deaggregation of compacted powders in capsules and tablets

What happens during the Dissolution step of the Oral Drug Absorption Sequence?

Dissolution of solid APIs into liquid molecules

What happens during the Diffusion step of the Oral Drug Absorption Sequence?

Diffusion of API molecules from the SI contents into the membrane capillaries

What happens during the Blood Transport step of the Oral Drug Absorption Sequence?

Transport of blood from intestinal membrane vessels to hepatic portal vein, the from the portal vein to the liver

What happens during the Liver Effects step of the Oral Drug Absorption Sequence?

Either:

A. Possible first pass metabolism

B. Transport of drug + metabolites from hepatic vein to the inferior vena cava then to the systemic bloodstream

What happens during the Absorption step of the Oral Drug Absorption Sequence?

Original API or Prodrug metabolite are absorbed in the Systemic bloodstream

What are the general four steps of Oral Drug Absorption?

Where do each of these steps occur?

When does first pass metabolism occur, if it does?

1. Disintegration (GUT, LUMEN)

2. Dissolution (GUT, LUMEN)

3. Diffusion (GUT WALL)

--FIRST PASS METABOLISM, IF IT OCCURS, IN LIVER--

4. Absorption (SYSTEMIC BLOOD STREAM)

What is Dissolution Rate?

Speed or rate at which drug substance dissolves in a medium

What is the Noyes-Whitney Equation?

What does it represent?

Represents dissolution rate

dc/dt = KS (Cs - Ct)

where,

dc/dt - dissolution rate, mg/s

K - dissolution rate constant, cm/sec

S - SA of exposed solid, cm2

D - diffusion coefficient of the drug in solvent, cm2/s

h - thickness of the diffusion layer (<0.05 mm thick)

Cs - saturation solubility, mg/mL

Ct - solubility at any time t, mg/mL

How does Surface Area affect Dissolution of oral dosage forms?

The smaller the particles of the same drug mass, the faster their dissolution

How does Surface Area affect Diffusion of oral dosage forms?

200x larger SA of SI compared to stomach lining explained why all swallowed substances that eventually reach the systemic bloodstream initially enter the blood in membrane capillaries of the Jejunum and Ileum

What four main formulation factors affect drug dissolution In Vivo?

1. DRUG PARTICLE SIZE for same amount of mass of API (smaller size, faster dissolution)

2. DISINTEGRATING AGENT

3. WETTING AGENT SURFACTANT increases fluid / solvent contact with drug particles

4. FILTER OR BULKING AGENTS depends on solubility

How does Bayer Advanced Aspirin compare to normal Aspirin?

ASPIRIN MICROPARTICLES are 90% smaller than normal, with this increased surface area having faster dissolution and shorter time required for pain relief

When In Vivo, does an Oral Suspension or Sugar Coated Tablets have faster dissolution and rapid bioavailability?

Oral Suspensions typically have faster dissolution and rapid bioavailability compared to Sugar Coated Tablets

How long is the segment of the Stomach to the end of the Ileum?

Which two areas are highly absorptive?

Stomach to End of Ileum is 10-20 feet long

Jejunum and Ileum have a HIGH absorptive area

What are the pH ranges for the 5 sections of the Upper GI Tract?

1. Stomach: 1 - 3

2. Pylorus: 2 - 4

3. Duodenum: 4 - 6 (1 ft.)

4. Jejunum: 5 - 7 (4-8 ft.)

5. Ileum: 6 - 8 (8-12 ft.)

What is the surface area of a normal human Stomach?

Jejunum and Ileum?

What is the equivalent surface area of the Jejunum and Ileum compared to?

Stomach - 1 m2

Jejunum and Ileum - 200 m2, which is compared to a single tennis court OR half of a basketball court

Which segment of the GI Tract does the most absorption occur?

Small Intestine (Jejunum and Duodenum)

What three factors are responsible for increasing drug diffusion rate into membrane capillaries?

1. LOWER VISCOSITY (more "flowing", greater "fluidity")

2. Drug not bound to material in contents

3. Shorter time of stomach-to-duodenum emptying

When would transit or emptying of the Stomach to the Duodenum be delayed or take longer?

If the gastric contents have:

- More Solid Chunks

- Higher Viscosity

- Fat > Protein > Carbohydrate

What does delayed gastric emptying lead to?

Leads to delayed drug contact with SI membranes, causing a delay in diffusion

How does the amount of Watery / Low Viscosity Fluid in the stomach affect diffusion and absorption?

The GREATER the Watery / Low Viscosity Fluid in the stomach, the FASTER the drainage through Pyloric Sphincter

This fluid carries small solid particles and dissolved drugs

This results in EARLIER diffusion and FASTER absorption

How does the Hepatic / Presystemic First Pass Effect occur?

Diffused drug in SI veins --> Hepatic Portal Vein --> Liver --> Hepatic Vein --> Systemic Blood Circulation

What is the Hepatic / Presystemic First Pass Effect?

Which drugs does it affect?

Decrease in the extent of absorption or bioavailability because of the first pass metabolism

Only affects drugs that hepatic enzymes have a high affinity or attraction for

Which routes of drug administration bypass the "first pass" effect / metabolism?

Sublingual (SL)

Buccal

Intravenous (IV)

Intramuscular (IM)

Subcutaneous (SC)

Transdermal

Inhalation

Rectal (partial bypass)