Modified Release Forms

Modified Release Forms

Describe dosage forms having drug release features based on time, course, and location that are designed to accomplish therapeutic or convenience objectives not offered by conventional or immediate release forms. For oral administration they most come in tablets or capsules.

Delayed Release Forms

Are designed to release the drug at time other than promptly after administration. The delay may be time based or based on the influence of environmental conditions like GI pH. Delayed release forms are enteric coated.

Extended Release Forms

Allow a reduction in dosing frequency necessitated by conventional dosage forms. They are designed to release their drug load in a controlled manner, at a predetermined rate, duration, and location to achieve and maintain optimum therapeutic blood levels of drug.

Other names for ER

Prolonged Release

Sustained Release

Long Acting Controlled Release

Prolonged Action

Repeat Action forms

Usually contain two single doses of medication. One for immediate release and the second for delayed release. Two layer tablets, for example may be prepared with one layer of drug for IR and the second layer designed for ER.

Targeted release forms

Describes drug release directed toward isolating or concentrating a drug in a body region, tissue, or site for absorption or for drug action

Sustained release

Slow release of drug over time.

Controlled release

Maintain consistent drug levels over time

Prolonged release

Constant drug levels no maintained

Rationale for Modified release forms

Market factor and patient factor

Improves patient compliance and reduce side effects

Advantages of Modified release forms

Protects acid labile drugs from gastric fluid

Prevents gastric distress due to irritation by the drug

Delivers drugs intended for local action in the intestines

Delivers drugs to their optimal absorption site in their max concentration

Provides delayed release of drugs

How do delayed release forms work

A thicker time dependent coating is used to protect the drug until it reaches the small intestine

Time dependent

Depends on the duration of the passage from stomach to intestines. If the tablet stays longer time than average it will start releasing in the stomach.

Thicker coating

pH dependent Coats

Will not dissolve or becomes permeable to water till a certain pH is reached. Some dissolve at pH 4.8 others at 5 or 6. No time control is provided. It depends on how fast your stomach empties.

Enteric coating

Film formers examples and pH they dissolve at

HPMC Phthalate - 5.5

Polyvinyl acetate phthalate - 5.5

Cellulose acetate phthalate - 6

Methacrylic acid copolymer - L 6; S 7

Plasticizer examples

Castor oil, diethyl phthalate, and dibutyl subacetate

Colorant and Opacifier examples

FD and C, iron oxide pigments

Vehicle examples

Water or other solvents

Enteric Coating Testing

Study disintegration in stimulated gastric fluid at 37C. If it is enteric coated disintegration should start occurring around 2 hours

Colon targeting

It is challenging to protect drug from degradation in the GI tract. A colon-targeted formulation may use a delayed-release coating that prevents drug release in the stomach and small intestine. Once it reaches the colon, the polysaccharide coating can be degraded or become permeable, allowing the drug to be released and appropriately absorbed.

Advantages to Extended-Release Forms

Less blood level fluctuation by eliminating peaks and valleys of blood levels

Reduction of dosing frequency more than one dose is loaded in the dosage form

Enhanced convenience and compliance with less dosing frequency

Reduction in side effects - do not reach high peaks

Reduction in health care costs

Disadvantages of ER

Loss of dose flexibility

Dose dumping

Things to consider when choosing ER

Drug and therapeutic indication must both be considered in determining the need for an ER product

Not all drugs are suited for formulation into ER products

Not all medical conditions require treatment by ER

Drug candidates

Exhibit neither very slow nor very fast rates of absorption of excretion. Drugs with very slow rates are inherently long acting. Drugs with very fast rates require large doses to be effective

They are uniformly absorbed from the GI tract. The drug must have a good aqueous solubility and maintain an adequate residence time in the GI tract without being destroyed. Drugs poorly absorbed are not good candidates.

They are administered in a relatively small doses. Large are too difficult to swallow

They possess a good margin for safety. Avoids serious side effects if dose dumping occurs.

Used in treatment of chronic rather than acute conditions.

What must be true for a successful ER product

Must release the loaded dose at a predetermined rate. The loaded drug must dissolve in GI fluids, maintain sufficient GI residence time, be absorbed at a rate that will replace the amount that is metabolized and excreted.

The rates that affect the presence of drug in the blood are

Drug Release Rate from Dosage form

Drug absorption Rate from GI tract

Drug elimination rate from the body

How to make a perfect ER product

Need to supply drug to reach therapeutic levels and maintain the level for a prolonged period of time. So an initial dose needs to be supplied to reach required blood levels followed by continuous steady release of a maintenance dose.

How can release rate reduction be acheived

Reducing the drug dissolution by controlling access of fluids into the dosage form.

Controlling the diffusion rate of drug out of the dosage form

Drug complexation

Extended Release Systems- Coated beads, granules, and microsphere:

These are small solid dosage forms that are coated with various thickness or various coating material. Then combined with each other along with uncoated forms. This combo can be placed in a capsule.

Extended Release Systems- multiple tablet system

Small tablets of varying release profiles are placed together in a capsule or compressed together. We can place several coated minitablets along with uncoated.

Extended Release Systems- microencapsulated drug

Microencapsulation is a process in which the drug is enclosed in a thing wall of coating

Extended Release Systems- Embedding drug in slowly eroding or hydrophilic matrix

The drug is granulated with a material that slowly erodes in GI fluids, progressively releasing the drug for absorption. Combining these granules with regular granules provides extended action. As the viscosity of the matrix is increased the release of drug is slowed down. Can use two layer tablet one with polymer for the maintenance dose and the other without for the loading dose.

Example of delaying material

Hydrophilic cellulose polymers: MC, HPMC, EF

Mechanism of action for Hydrophilic Matrix Systems

Hydration of cellulosic polymer

Gel formation on the tablet surface

Erosion of gel layer

Drug release

Embedding Drug in inert Plastic Matrix

The drug is granulated with an inert plastic material such as polyethylene, PVA, polymethacrylate, and compressed into tablets. The drug is slowly released from the matrix by diffusion, leaching from the matrix and leaving it as a skeleton that can be excreted in the feces.

Complex formation

The drug is reacted with other chemical agent. The resulting complex has lower solubility and slow dissolution and absorption. The drug release from resin-drug complex depends on the pH and electrolyte concentration in the GI fluids. Release is greater in he acidity of the stomach.

Examples of complex formations

Hydrocodone polistirex, phenteramine resin

What is the Osmotic pump system

Core tablet is coated by a semipermeable membrane coating having a 0.4mm hole produced by laser. The drug can be mixed with osmotic substance or, the core table has two layers, one containing the drug and the other containing a polymer osmotic agent. active layer + push layer. System is operated by osmotic pressure.

MOA of osmotic pump system

When the tablet is swallowed, the semipermeable membrane allows water to enter into the core, dissolving or suspending the drug. As pressure increases in the osmotic layer, it pumps the drug solution through the orifice. Only the drug in solution gets to leave. The tablet is designed so that only few drops of water go into the tablet per hour. The drug release is constant as long as the osmotic gradient is constant.

How to alter drug release rate of osmotic pump system

Alter surface area, thickness/composition of the membrane, and/or diameter of the release orifice. The drug release is not affected by GI pH, food, GI motility. The shell is eliminated intact in the feces.