Calling the Shots: Innovation in Controlled-Release Injectables - Pharmaceutical Technology

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Calling the Shots: Innovation in Controlled-Release Injectables
High demand could lead to innovation in controlled-release injectables.


Pharmaceutical Technology
Volume 35, Issue 7, pp. 36-41

The polymeric matrix controls drug release by acting as a diffusion barrier that determines the rate at which the drug payload dissolves. The barrier also controls the rate at which the dissolved payload diffuses from the matrix. Formulators could modify the polymeric matrix to create release mechanisms that range from diffusion-based to degradation-based systems.

The release rate from a microsphere partly depends on the composition of the polymer. For example, the release rate from a PLGA microsphere is affected by the ratio of lactide to glycolide, says Darvari. Molecular weight is an important factor, too. Polymers with high molecular weights generally release their payloads at a slower rate, says Mathew Cherian, director of global research and development for Hospira. The polymers' hydrophilicity, hydrophobicity, particle morphology, and surface charge also can affect the drug's release profile.

Polymeric microsphere systems allow for a broad range of release profiles, including sustained release with zero-order and first-order kinetics, delayed release, and pulsatile release. The polymer composition also can be modified to provide an initial release of drug substance before the delivery rate stabilizes at a lower rate. "The degree of polymerization, and consequently the molecular weight, modulates the release rate," says Cherian. "By using two or more molecular-weight ranges in separate steps, during formulation, multiple release rates can be obtained."

The most common goal, especially for treating chronic diseases, is a constant- or sustained-release profile. Polymeric microspheres can provide sustained drug release for one week, or for as long as a month. Some companies are developing products with release profiles of three months or more. Life-science company Peptron has a three-month formulation of leuprolide in clinical trials. Eligard (leuprolide) from Atrix Laboratories has a three-month profile. Debiopharm has a triptorelin-embonate formulation capable of delivering for as long as six months.

In addition to the wide range of release profiles that they enable, polymeric microspheres have other advantages. The synthetic polymers can be readily synthesized in a narrow range of properties (e.g., molecular weight, viscosity, and comonomer ratio). Then the classification and adherence to standards could be reliably achieved by common methods of analysis.

PLGA polymers also are nonimmunogenic. Because they eventually degrade to their original monomeric components, the microsphere can act as an injectable depot system without the need for removing the matrix once the depot is depleted.

Microspheres also can enhance the safety of potent drugs by preventing an initial dosage spike upon administration. By encapsulating the drug and controlling its release, microspheres avoid the spike in blood levels seen after the injection of unencapsulated drugs.


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