Modified-Release Drug Delivery

Pharmaceutics II

What two predetermined rates do we aim to achieve in modified release drug delivery?

Temporal and spatial

In first order release, what does the dissolved drug vs time passed graph look like?

It appears as a curved line

In zero order release, what does the dissolved drug vs time passed graph look like?

The line is straight

In first order release, what does the concentration of drug in blood and time passed graph look like?

It goes up, and then comes down

In zero order release, what does the concentration of drug in blood and time passed graph look like?

It goes up and then plateaus

Which modified release dosage form is zero order?

Controlled release

Which modified release dosage form is 1st order?

Sustained release

Dose dumping

Occurs when a modified dosage form releases its contents all at once, might happen if it is broken or crushed.

What gastrointestinal conditions may make modified release products difficult?

GI narrowing, shortened bowel, and bariatric surgery

Matrix system (monolithic)

The API is uniformly dispersed within the matrix forming agent

Hydrophilic soluble matrix system

Water soluble matrix leads to erosion of dissolution of the matrix, causing the drug to leave the matrix.

Hydrophilic swellable matrix system

Still water soluble, the matrix hydrates, swells, and forms a gel layer, causing dissolution and diffusion of the drug through the gel layer.

Hydrophobic insoluble matrix

Water and GI fluid go into the matrix and dissolves and diffuses the drug through the insoluble matrix. The insoluble matrix stays in tact.

Purpose of PEG in insoluble matricies

Creates a pore for water to go through and get into the wax to dissolve the drug

What is the mechanism of drug release in a reservoir system?

The drug dissolves and then diffuses through a membrane.

What could make up the core of a reservoir system drug release product?

Drug and excipients or a matrix

Mechanism of release for osmotic (OROS) systems

Solvent activated push. Water from the patient goes into the laser drilled hole and goes through a movable partition, creating pressure. This pressure raises the partition, causing the drug to be pushed out of the hole in a specific rate.

What order of reaction are OROS systems?

Zero order. It is constant release due to pressure.

Reason for delayed release in Aspirin EC 81mg

Prevent stomach irritation

Reason for delayed release in Prilosec OTC

Protect the drug from the low pH of the stomach

Reason for delayed release in Omega 3 centrum ProNutrients

Prevent regurgitation and irritation of the esophagus

Reason for delayed release in Dulcolax

Provide local action in the intestine

What makes up a biphasic repeat action drug?

Coated beads (CR), and uncoated IR beads or IR tablet

What makes up a triphasic repeated action drug?

Drug overcoat that is IR, then OROS mechanism inside with a lower concentration of drug at the top (near the hole), and a higher concentration of drug below it.

Composition of multilayer Claritin D

Outer layer (IR) has loratadine and pseudoephedrine

Core (ER) has pseudoephedrine

Loratadine is only in the outer layer because it has a longer half life.

Ion-exchange resin

Resin contains drug and in the body the ions of the body exchange for the drug

How to calculate dose of drug that should be given orally when compared to the IV dose

AUC (oral)/AUC (iv) x Dose(iv)/Dose(oral)

Based on aqueous solubility, what drugs have optimal properties for controlled release?

Drugs with an aqueous solubility more than 0.1mg/mL and less than 1000mg/mL

What type of transport is better for controlled release?

Passive transport

Over how many hours is a half life too long to consider a controlled release?

8

At what dosage are drugs unsuitable for controlled release?

Over 500mg

What half life range is optimal for controlled release products?

2-8 hours.

Major challenges of modified drug release

Unpredictable gastric emptying time, GI transit time, presence of food, variations in GI pH and motility, limited contact at the time of absorption

Mechanisms to increase GI residence

Floating system (low density system)

High density system

Mucoadhesive or bioadhesive systems

When to use caution in modified release dosage forms?

In pateints with preexisting GI narrowing, shortened bowel, or other GI issues.