Abstract
This study optimized the preparation of electrosprayed microspheres containing leuprolide and developed an in vitro–in vivo correlation (IVIVC) model that enables mutual prediction between in vitro and in vivo dissolution. The pharmacokinetic (PK) and pharmacodynamic (PD) study of leuprolide was carried out in normal rats after subcutaneous administration of electrosprayed microspheres. The parameters of the IVIVC model were estimated by fitting the PK profile of Lucrin depot® to the release compartment of the IVIVC model, thus the in vivo dissolution was predicted from the in vitro dissolution. From this correlation, the PK profile of leuprolide was predicted from the results of in vivo dissolution. The IVIVC model was validated by estimating percent prediction error (%PE) values. Among prepared microspheres, an optimal formulation was selected using the IVIVC model. The maximum plasma concentration and the area under the plasma concentration–time curve from zero to infinity from the predicted PK profile were 4.01 ng/mL and 52.52 h·ng/mL, respectively, and from the observed PK profile were 4.14 ng/mL and 56.95 h·ng/mL, respectively. The percent prediction error values of all parameters did not exceed 15%, thus the IVIVC model satisfies the validation criteria of the Food and Drug Administration (FDA) guidance. The PK/PD evaluation suggests that the efficacy of OL5 is similar to Lucrin depot®, but the formulation was improved by reducing the initial burst release.
Highlights
Sustained release (SR) injections containing poly (d,l-lactide-co-glycolide) (PLGA) and its copolymers have been widely used because of their biocompatibility and their ability to achieve a variety of therapeutic benefits, including no need for daily administration, more consistent bioavailability, low relapse rates, and improved patient compliance
The leuprolide used in this study is a synthetic nonapeptide gonadotropin-releasing hormone (GnRH) analog that acts as a potent reversible inhibitor of gonadotropin secretion through suppression of testicular steroidogenesis
According to the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q3C guideline, methylene chloride is classified as a class 2 solvent that should be limited in pharmaceutical products because of its inherent toxicity
Summary
Sustained release (SR) injections containing poly (d,l-lactide-co-glycolide) (PLGA) and its copolymers have been widely used because of their biocompatibility and their ability to achieve a variety of therapeutic benefits, including no need for daily administration, more consistent bioavailability, low relapse rates, and improved patient compliance. It enables the acquisition of a high yield, provides easy control of drug particle size, and reduces the risk of heat-induced denaturation of the peptide drugs [4,5] Despite these advantages, formulation study of leuprolide using the electrospray method has never been reported. D’Souza et al introduced IVIVC on long acting microspheres of olanzapine [6] They established Level A IVIVC through in vitro release data obtained from a dialysis-based method using deconvolution and fractional area under the plasma concentration-time curve (AUC) method. While most traditional IVIVCs comprise retrospective research based on in vivo results, this study can predict the PK profile during the formulation study using in vitro results with minimal in vivo results For this reason, this paper is expected to provide a method both financially and timely efficient to the pharmaceutical industry. PK and pharmacodynamics (PD) of the leuprolide after subcutaneous (SC) administration of trial formulation was evaluated
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