PHA619 LEC: Solid Modified Release Dosage Forms

Modified Release

Dosage forms having drug-release features based on time, course, and/or location.

Modified Release

Designed to accomplish therapeutic or convenience objectives not offered by conventional or immediate-release forms.

Extended Release/Sustained Release

Allows a reduction in dosing frequency from that necessitated by a conventional dosage form, such as a solution or an immediate-release dosage form making the drug available over an extended period after ingestion

Extended Release/Sustained Release

Designed to release their medication in a controlled manner, at a predetermined rate, duration, and location to achieve and maintain optimum therapeutic blood levels of drug.

Extended Release/Sustained Release

• The duration of drug action is prolonged for longer time

• Eg. Sustained release dosage form of any antipsychotic drug

Delayed Release

Designed to release the drug at a time other than promptly after administration.

Delayed Release

The delay may be time based or based on the influence of environmental conditions, like gastrointestinal pH.

Delayed Release

Most _ products are enteric-coated tablets or capsules designed to pass through the stomach unaltered, later to release their medication within the intestinal tract

Delayed Release

Onset of drug action starts at a later phase ○ Eg. Enteric coated tablets (special coating) are known to show the action when dosage forms reach small intestine.

Delayed Release

Protect the drug from degradation on the low pH environment of the stomach or to protect the stomach from irritation by the drug.

Repeat Action

Usually contains two single doses of medication, one for immediate release and the second for delayed release.

Repeat Action

Two-layer tablets, for example, may be prepared with one layer of drug for immediate release with the second layer designed to release drug later either as a second dose or in an extended-release manner

Targeted Release

Directed toward isolating or concentrating a drug in a body region, tissue, or site for absorption or for drug action.

Less Fluctuation in Drug Blood Levels

Advantage of Extended Release

Eliminate peaks and valleys of blood levels with the ability to control the rate of release.

Frequency Reduction in Dosing

Advantage of Extended Release

Frequently deliver more than a single dose. Hence may be taken less often than conventional forms.

Enhanced Convenience and Compliance

Advantage of Extended Release

• With less frequency of dosing, patience is less apt to neglect to take a dose.

• Greater convenience with day and night administration.

Reduction in Adverse Side Effects

Advantage of Extended Release

• Fewer blood level peaks outside the therapeutic range and into the toxic range, adverse side effects are less frequent.

Reduction in Overall Healthcare Costs

Advantage of Extended Release

Although initial cost may be greater than conventional forms, overall cost of treatment may be less because of enhanced therapeutic benefit, fewer side effects, and reduced time for healthcare personnel to dispense and administer drugs, and monitor the patient.

Improved Patient Compliance

Advantage of Extended Release

By reducing frequency of medications or administration

Cost Effective

Advantage of Extended Release

The production cost is more for the medication however the cost for entire therapy is reduced drastically

Advantages

Better Bioavailability for the Drugs

Use of Advanced Technology

Avoidance Irregular Drug Plasma Concentration

Disadvantage

Loss of flexibility because there will be an adjustment of the drug dose and dosage regimen. Risk of sudden and total drug release or dose dumping due to failure of technology

Coated Beads

1 mm in diameter.

Combined to have three or four release groups among the more than 100 beads contained in the dosing unit.

Coated Beads

Provides the different desired rates of sustained or extended release and the targeting of the _ to the desired segments of the gastrointestinal tract

Coated Beads

An example is Spansule capsule.

Pellets

Using conventional pan coating or air suspension coating, a solution of the drug substance is placed on small inert nonpareil seeds or beads (pellets) made of sugar and starch or on microcrystalline cellulose spheres.

Pellets

Good tolerability and stable therapeutic effect. Pellet-released active ingredients may offer a higher bioavailability than usual drugs.

Nonpareil (pellet) seeds - 425 to 850 mm.

Pellets

Example: Doryx

Granules

Receive varying coats of a lipid material like beeswax, carnauba wax, glyceryl monostearate, or cetyl alcohol or a cellulosic material like ethylcellulose

Granules

_ of different coating thicknesses are blended to achieve a mix having the desired drug-release characteristics

When properly blended, the _ may be placed in capsules or formed into tablets

Granules

Example: Pentasa (mesalamine)

Microspheres

More durable during production than sugar-based cores

Microcrystalline cellulose spheres - 170 to 600 mm

Microspheres

The drug can be encapsulated or entrapped.

The polymeric composition of microspheres can be classified into two types: natural and synthetic

Microspheres

Example: Vitamin C and Bio-Quercetin Phytosome Supplements

Natural Polymeric Microspheres

Derived polymers that have been prepared by several techniques like coacervation phase separation, emulsion polymerization, modified quasi emulsion solvent diffusion, emulsion cross-linking, thermal denaturation, emulsification solvent evaporation, spray drying and suspension polymerisation.

Synthetic Polymeric Microspheres

Frequently used in clinical practice and find application in a wide range of medical applications. Among other applications, microspheres are being used as bulking agents, embolic- or drug-delivery particles.

Multi-Tablet System

Small spheroid compressed tablets 3 to 4 mm in diameter may be prepared to have varying drug-release characteristics.

Multi-Tablet System

They then may be placed in gelatin capsule shells to provide the desired pattern of drug release.

Each capsule may contain 8 to 10 mini tablets, some uncoated for immediate release and others coated for extended drug release

Microencapsulated Drugs

is a process by which solids, liquids, or even gases may be enclosed in microscopic particles by formation of thin coatings of wall material around the substance.

Two-layer tablets

One layer containing the uncombined drug for immediate release and the other layer having the drug embedded in a hydrophilic matrix for extended release (ER)

Three-layer tablets

Both outer layers containing the drug for immediate release

Embedding Drug in Inert Plastic Matix

The drug is granulated with an inert plastic material (polyethylene, polyvinyl acetate, or polymethacrylate) and the granulation is compressed into tablets

Complex Formation

Some drug substances, when chemically combined with certain other chemical agents, form complexes that may be only slowly soluble in body fluids, depending on the pH of the environment.

Ion-exchange Resins

A solution of a cationic drug may be passed through a column containing an ion-exchange resin, forming a complex by the replacement of hydrogen atoms.

Ion-exchange Resins

The resin-drug complex is washed and may be tableted, encapsulated, or suspended in an aqueous vehicle.

The release of the drug depends on the pH and electrolyte concentration in the gastrointestinal tract.

Osmotic Pump

Composed of a core tablet surrounded by a semipermeable membrane coating having a 0.4-mm-diameter hole

Active layer

Two core tablet layers

containing the drug

Push layer

Two core tablet layers

containing a polymeric osmotic agent

LEVEL A

Predictive mathematical model for the relationship between the entire in vitro dissolution and release time course and the entire in vivo response time course

LEVEL B

Predictive mathematica model of the relationship between summary parameters that characterize the in vitro and in vivo time courses

LEVEL C

Predictive mathematical model for the relationship between the amount dissolved in vitro at a particular time and a summary parameter that characterizes the in vivo time course

Transdermal patches

• A backing or support layer that protects the patch

• A drug layer that might be in the form of a solid gel reservoir or in a matrix

• A pressure-sensitive adhesive layer

• A release liner or protective strip that is removed before placing the patch on the skin. In some cases, the adhesive layer may also contain the active drug

Parenterals

This dosage form includes microspheres, liposomes, drug implants, inserts, drug-eluting stents, and nanoparticles.

These formulations are designed by entrapment or microencapsulation of the drug into inert polymeric or lipophilic matrices that slowly release the drug, in vivo

For the duration of several days or up to several years

Implants

Long-acting dosage forms that provide continuous release of the drug, often for periods of months to years

Placed subcutaneously for systemic delivery

Place in specific regions of the body for local delivery

Made by compression, melting or sintering; usually drug and rate-controlling excipients

Ex. pellets, resorbable microparticles or microspheres, polymer implants, liquid-gel/solid implants, metal/plastic implants

Liposomes

Composed of small vesicles of a bilayer of phospholipid encapsulating 1 or more an aqueous base/compartments (ranging from about 0.02 to 10 mm in diameter)

Stealth Liposomes

Result of liposome research that can avoid detection by the body's immune system (RES — Reticuloendothelial System)

Prepared with polyethylene glycol or PEG on the outside of the membrane as coating