Drug formulations are developed to deliver drugs for the maximum benefit to patients. The maximum benefit to the patients occurs when the drug is released correctly in a predetermined manner to maintain the dose between the minimum effective concentration and upper level toxic concentration, the therapeutic dose range . The underlying assumption of using the drug dissolution property for quality control is that different formulations are expected to have the same in vivo drug absorption property as long as the in vitro drug release kinetics are the same. For generic formulations, however, the similar in vitro dissolution property does not guarantee that they would have the same in vivo absorption properties. This is simply because the in vitro dissolution property depends on the dissolution method used. The issue of using in vitro dissolution property as a means to compare different formulations becomes complicated for non-oral formulations such as sustained release (SR) parenteral depot formulations. Of the many parenteral depot formulations, microparticle formulations have been most frequently used and are the focus of this study. The goal of this project is to design and develop new in vitro dissolution apparatus that can incorporate in vivo properties, i.e., conditions that a formulation may encounter after parenteral administration. There are three specific aims. The three aims will be conducted simultaneously, as they are interdependent. The first specific aim is to design and develop new in vitro dissolution apparatuses for testing parenteral SR formulations. These apparatus will be designed to incorporate into the existing USP apparatus type 4 for ease of adaptation with current testing equipment. The second specific aim is to formulate SR triptorelin microparticles using microfabrication method and compare these with the currently existing clinical product. The comparison will be between Akina's novel hydrogel-template based microfabrication method and conventional double emulsion technique as well as with Trelstar, which is a commercially available triptorelin microparticle to be used as a control formulation. The third specific aim is to conduct in vitro dissolution studies of the prepared formulations and identify the most sensitive dissolution method. The formulations prepared in the second Aim will be tested by the methods developed as part of the first aim in order to identify a dissolution method which discriminates the differences between the SR formulations. The ability to distinguish differences in SR formulations is important as the physicochemical differences relevant to the formulation may affect the bioavailablity of the drug. The successful completion of this project is expected to produce a new dissolution apparatus which can aid in distinguishing formulations generated under different manufacturing conditions. This dissolution assay will aid overall public health by improving the capability to ensure that all injectable SR formulations have the appropriate bioavailability and release profiles for sustained therapeutic dose.

Public Health Relevance

The primary goal of this project is to develop a novel dissolution assay apparatus which is easily incorporated into the currently existing USP-4 apparatus system to allow for more accurate discrimination of formulation differences amongst sustained release parenteral microparticles. This apparatus will be tested by comparing triptorelin formulations generated either by double emulsion technique or by a novel hydrogel template technique and comparing these to the commercially available Trelstar? product. The developed apparatus will improve the capability of assays to differentiate injectable SR formulations and ensure that they have the appropriate bioavailability and release profiles for sustained applications of therapeutic doses

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZFD1-SRC (99))
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Akina, Inc.
West Lafayette
United States
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Garner, John; Skidmore, Sarah; Park, Haesun et al. (2018) Beyond Q1/Q2: The Impact of Manufacturing Conditions and Test Methods on Drug Release From PLGA-Based Microparticle Depot Formulations. J Pharm Sci 107:353-361
Garner, John; Skidmore, Sarah; Park, Haesun et al. (2015) A protocol for assay of poly(lactide-co-glycolide) in clinical products. Int J Pharm 495:87-92