Solid Oral MR Dosage Forms - Delayed Release Dosage Forms

Delayed release (DR) dosage forms

designed to release the drug at a time or place other than promptly after administration

What causes the delay in DR dosage forms

• time

• influence of environmental conditions, e.g. GI pH

Ways to formulate DR dosage forms

• gastro-resistant or enteric coatings

• colonic drug delivery (bacterially triggered)

• chronotherapy

Gastro-resistant/enteric coatings mechanism

• dissolves only at higher pH

• remain insoluble in acidic stomach pH

• drug is released once reaching small intestine or with higher pH-trigger thresholds

Uses of gastro-resistant/enteric coatings

• to protect stomach from irritating drugs

• to protect acid-labile drugs from gastric degradation

• to target drug release to the small intestine or colon

Polymers used for gastro-resistant/enteric coatings

• EudragitⓇ S (methacrylic acid copolymer B)

• cellulose acetate phthalate

• polyvinyl acetate phthlate

• hydroxypropyl methylcellulose phthalate

Limitations of gastro-resistant/enteric coatings

• dosage form may pass through high pH region quickly

• some patients never reach pH or 7, leading to failure of coat dissolution

• if dissolution does not occur, dosage form may pass intact in the stool and release no drug

Bacterially triggered system mechanism

uses colonic microbiota to initiate drug release and does not depend on pH

Bacterially triggered system characteristics

• dosage form is coated with a biodegradable component

• biodegradable components are resistant starch such as ethyl cellulose that can only be broken down by colonic bacteria

• when dosage form reaches colon, bacterial enzymes degrade starch to create pores/channels in coating

Chronotherapy mechanism

involves designing modified-release oral dosage forms to release drug at specific times of day to match the biological rhythms of disease symptoms rather than maintaining constant drug levels

Chronotherapy layers

• outer delayed-dissolving layer controlling lag time

• inner immediate-release core that rapidly releases drug once barrier dissolves

Chronotherapy example

inflammatory conditions show circadian variation, with symptoms worsening in early/later hours

• e.g. rheumatoid arthritis worsening in early morning

• take prednisolone at bedtime, releases in morning when symptoms are heightened

Small intestinal targeted (enteric) system site of release

can release drug load in small intestine

Colonic system site of drug release

release their drug here and may be able to extend release throughout the large intestine

Gastroretentive system site of release

retained in stomach and should release drug in stomach and small intestine

ER system site of release

can theoretically release drug throughout GI tract

Single-unit modified-released dosage forms

• consist of single entity, usually tab

• aka monolithic dosage form

Manufacturing advantages of single-unit modified-release dosage forms

• can be produced using conventional techniques

• includes direct compression and film coating

Single-unit modified-release limitations

• single-unit tablets may remain in stomach for prolonged period when taken with food

• if a drug is intended to act in small or large intestine, delaying gastric emptying may prevent drug from reaching site of action

• can lead to dose dumping

Multiple-unit modified-release dosage form

composed of pellets or granules filled into a capsule

Multiple-unit modified-release dosage form advantages

• more uniform and reproducible gastric emptying

• reduced risk of dose dumping

• less affected by gastric motility with food

Multiple-unit modified-release dosage form limitations

require more complex process to control and scale-up

Multiple-unit modified-release dosage from customized release profile

ability to achieve customized release profiles by applying different polymer coatings to different pellet populations

Labelling requirements for modified-release dosage forms

• must label DR and state that tablets are enteric coated

• ER must specify dosing interval

  • 12 vs. 24 hour

  • state which in vitro drug-release test the product complies

What must be noted when compounding MR dosage forms?

• MR tabs/caps are generally not suitable for compounding

• patients fed via enteral nutrition may receive conventional or MR medication

Patient counseling for MR dosage forms

• do not crush or chew

• ghost tablets may appear in stool for insoluble and oral osmotic systems

• dose & dosage frequency of modified drug-release products

• do not use interchangeably of concurrently with IR forms of same drug