Injectable Polymeric Particulate System In Vitro Testing Challenges
Biodegradable microparticles formulated using biodegradable polymers, such as polylactide (PLA), poly (lactideco- glycolide) (PLGA) (1Y6), gelatin (7Y9) and albumin have been used as carriers for small molecules and biologically active peptides and proteins. In addition to being biodegradable, other advantages include reduced frequency of administration, enhanced patient compliance, sustained drug release, reduced dosage and less systemic side effects. PLA and PLGA have been approved for human use by the United States Food and Drug Administration (US FDA) as surgical sutures, implantable devices and other drug delivery systems.
Once injected intramuscularly or subcutaneously, these formulations release the encapsulated therapeutic agent over long periods of time depending on polymer molecular weight and hydrophilicity, drug loading and particle size and morphology
Because these formulations release drug over long periods of time, evaluation of release from microparticles requires long-term studies, whether they be in vivo animal studies or in vitro testing using physiologic buffers at 37oC. Because of the labor and expense involved with assessing in vivo drug release, in vitro drug release studies at 37oC (physiological temperature) have gained increasing importance.
Unlike controlled release oral formulations, there are no regulatory standards for parenteral microparticle delivery systems. Also, the current United States Pharmacopeia (USP) apparatus for in vitro release testing was designed mainly for oral and transdermal products and is not directly applicable for parenteral products administered subcutaneously or intramuscularly.
In vitro release studies are generally performed to accomplish one or more of the following aims:
Set regulatory specifications for the products for quality control (QC) purposes to ensure in vivo product performance
Substantiation of label claim and evaluation of potential dosage variations
Monitor product lot-to-lot consistency to ensure products’ “sameness”
Assist formulation development, monitoring the changes in manufacturing process, substitution of excipients or equipment
Assess in vivo stability and possible in vitro-in vivo correlation
Over the past decade, there have been attempts to compare in vitro testing methods to study drug release from parenteral biodegradable microspheres. There are two main techniques: dialysis and flow-through cell methods that are successfully applied for in vitro release rate testing studies from injectable polymeric particulate systems.
Two-step dialysis assay protocols to measure the in vitro release rate of encapsulated pharmaceutical actives from liposome and polymeric particulate systems have been developed and are available. These methods have been successfully used for evaluation of product lot-to-lot consistency and stability testing programs.