Summary

• RISPERDAL CONSTA is a combination of extended-release microspheres for injection and diluent for parenteral use.¹
• To form the microspheres using Medisorb^® technology, risperidone is encapsulated in polylactide coglycolide, a biodegradable polymer.² Following an intramuscular injection, The polymer gradually breaks down predominantly into naturally occurring glycolic acid and lactic acid, releasing risperidone into the body at a controlled rate. Glycolic acid and lactic acid are eliminated as carbon dioxide and water.³

Drug Release Profile¹

The drug release profile from a single intramuscular injection of RISPERDAL CONSTA consists of a small initial release of drug (< about 1% of the dose), followed by a lag time of 3 weeks. The main release of drug starts from 3 weeks onwards, is maintained from 4 to 6 weeks, and subsides by 7-8 weeks following the intramuscular injection.

The combination of the release profile and the dosage regimen (intramuscular injection every two weeks) results in sustained therapeutic plasma concentrations. Steady-state plasma concentrations are reached after 4 injections and are maintained for 4 to 6 weeks after the last RISPERDAL CONSTA. The elimination phase is complete approximately 7 to 8 weeks after the last intramuscular injection.

PUBLISHED AND UNPUBLISHED LITERATURE

Rios (2003)² described the development of RISPERDAL CONSTA for intramuscular administration, using the combination of risperidone and Medisorb^® microsphere technology developed by Alkermes, Inc.

In the development of RISPERDAL CONSTA, risperidone is encapsulated in polylactide coglycolide (PLG), a biodegradable polymer. The ratio of lactic acid and glycolic acid in the polymer is a significant factor in the rate of drug release from the formulation.

Microspheres are formed by first dissolving risperidone and PLG in an organic solvent mixture and then mixing it with an aqueous solution to form an emulsion. The solvent is removed, and the polymer microspheres containing risperidone are dried into a free-flowing powder. The resulting powder is packaged into a vial. The powder must be reconstituted prior to intramuscular injection with the aqueous-based diluent provided in the dose pack. Hydrolysis of the microspheres results in a gradual breakdown of the polymer, thereby releasing risperidone.

The polymer gradually breaks down predominantly into naturally occurring glycolic acid and lactic acid, releasing risperidone into the body at a controlled rate. Glycolic acid and lactic acid are eliminated as carbon dioxide and water Ramstack et al (2003).³ The polymer has been used in other pharmaceutical products and has been approved by the FDA as a safe product for use in such products.

Further information regarding the Medisorb^® technology can be obtained on the Alkermes, Inc. website at https://www.alkermes.com/research-and-development#technologies.⁴

Lasser et al (2002)⁵ conducted an in-vitro degradation study evaluating the release of drug from the RISPERDAL CONSTA microspheres. The microspheres were exposed to physiological pH and temperature during which time degradation was measured by polymer molecular weight, release of drug, and microscopy. The Table: Degradation of Microspheres provides the drug release profile measured during the study for RISPERDAL CONSTA microspheres:

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 16 August 2024.