Biopharmaceutics of modified release drug products Dr. Jwan Mohammed

Advantages and disadvantages of MR Types of MR Introduction Conventional drug formulation (IR) Modified release drug delivery (MR) Advantages and disadvantages of MR Types of MR Rationale of MR formulations

Conventional drug formulation Most conventional (also named as immediate-release, IR) oral drug products, such as tablets and capsules, are formulated to release the active pharmaceutical ingredient (API) immediately after oral administration. immediate-release products generally result in relatively rapid drug absorption and onset of action (time by which the pharmacologic effect of the drug starts).

Modified release drug delivery Modified-release (MR) deals with the use of delivery devices that can release the drug into the patient body at a predetermined rate or at a specific time or with specific release profiles. MR drug product is a products that alter the timing and/or rate of release of the drug substance in the formulation. A modified-release dosage form can provide therapeutic results and/or convenience for the patient that can not be offered by conventional dosage forms such as solutions, ointments, or promptly dissolving dosage forms.

The objective of MR drug products for oral administration is to control the release of the therapeutic agent and thus control drug absorption from gastrointestinal tract. As long as the drug release rate is less than the drug absorption rate the release rate is the rate determining step This leads to reducing fluctuation of drug plasma concentration and reducing dose frequency or night time dosing This improves patient compliance Different types of MR drugs are available

Advantages of MR drug products Release of drug at predetermined rate. Maintain optimal and effective drug level for prolonged duration Minimal fluctuation in plasma drug concentration. Reducing side effects Reducing frequency of dosing Avoidance of night time dosing Increasing patient compliance

Disadvantages of MR products Higher cost Unpredictable or poor in vitro-in vivo correlation Dose dumping; this is a phenomenon whereby relatively large quantity of drug in a controlled-release formulation is rapidly released, introducing potentially toxic quantity of the drug into systemic circulation. Usually, the dose-dumping comes from the fault of formulation design. Reduced potential for dose adjustment

Types of MR drug products: 1. Extended release drug product Extended-release drug products is a dosage form that allows at least a twofold reduction in dosage frequency as compared to that drug presented as an immediate-release (conventional) dosage form. In these formulations drug activity can continue for a longer time than conventional drugs. Examples of extended-release dosage forms include controlled-release, sustained-release, and long-acting drug products.

sustained-release drug product A sustained-release drug product is an extended release product that is designed to release a drug at a predetermined rate for the constant drug concentration maintaining during a specific period of time. Usually, the drug may be delivered in an initial therapeutic dose, followed by a slower and constant release. The purpose of a loading dose is to provide immediate or fast drug release to quickly provide therapeutic drug concentrations in the plasma.

The rate of release of the maintenance dose is designed so that the amount of drug loss from the body by elimination is constantly replaced. With the sustained release product, a constant plasma drug concentration is maintained with minimal fluctuations. The drug release profile is usually a first order kinetics which means that release rate is dependent on the concentration of the drug in the release site (i.e. GIT), the release rate is fast at the beginning then reduces with time when the concentration increases.

Controlled release drug products A controlled release drug product is also an extended release product in which the release rate is well controlled The drug release profile is usually a zero order kinetics which means that release rate is independent on the concentration of the drug in the release site (i.e. GIT)

2. Delayed-release drug products A dosage form that releases a discrete portion/portions of drug at a specified time rather than the promptly release after administration. Enteric-coated dosage forms are common delayed-release products (eg, enteric-coated aspirin and other NSAID products). usually the enteric-coating materials are polymer-based barrier applied on oral medicine. This coating may delay release of the medicine until after it leaves the stomach, the purpose of enteric coating is either for drug protection under harsh pH circumstance of stomach or for prevention of irritation on cell membrane from the drug itself.

3. Targeted-release drug products A dosage form that releases drug at or near the intended physiologic site of action. It could be regarded as a type of delayed release products. Targeted-release dosage forms may have either immediate- or extended-release characteristics. An example of targeted-release drug product is mesalamine delayed release which is used to treat ulcerative colitis. It is coated for drug release in terminal ileum

4. Orally disintegrating tablets(ODTs) Orally disintegrating tablets(ODTs). ODTs have been developed to disintegrate rapidly in the saliva after oral administration. ODTs may be used without the addition of water. The drug is dispersed in saliva and swallowed with little or no water. Loratadin is available as ODTs.

Comparison of Drug Release profiles

Plasma drug concentration of a sustained release and a regular-release product. Note the difference of peak time and peak concentration of the two products.

Immediate release and delayed release profiles

examples Dose of diclofenac conventional tablet is 50 mg three times a day while the dose for diclofenac extended release is 100 mg once daily. Nifedipine is calcium channel blockers available as conventional tablet and controlled release Adalat is a conventional tablet of nifedipin taken 10 mg three times a day while Adalat Oros is a controlled release tablet taken 30-60 mg once daily

The rationale of modified drug delivery The basic rationale for MR is to optimize the biopharmaceutics, pharmacokinetic and pharmacodynamics properties of a drug to improve the efficacy of drugs with improved patient compliance, better control of plasma drug levels and less frequent dosing. The dosing interval can be increased to reduce the frequency of dosing This is accomplished by reducing the rate of absorption by reducing the rate of drug release (i.e. controlling the release of the drug)