In vitro–in vivo correlation from lactide-co-glycolide polymeric dosage forms

Abstract

The objective of this study was to compare the in vitro behavior of four long-acting subcutaneous risperidone formulations with in vivo performance, with the intent of establishing an IVIVC. Two copolymers of PLGA (50:50 and 75:25) were used to prepare four microsphere formulations of risperidone, an atypical antipsychotic. In vitro behavior was assessed at the physiological temperature (37 °C) using the ‘modified dialysis’ technique. The in vitro release profile demonstrated rank order behavior with Formulations A and B, prepared using the 50:50 copolymer, exhibiting rapid drug release, while Formulations C and D, prepared using 75:25 PLGA, released drug in a slower manner. In vivo profiles were obtained by two approaches, i.e., deconvolution using the Nelson–Wagner equation (the FDA recommended approach) and using fractional AUC. With both in vivo approaches, the 50:50 PLGA preparations released drug faster than the 75:25 PLGA microspheres, exhibiting the same rank order observed in vitro. Additionally, profiles for the four formulations obtained using the deconvolution approach were nearly superimposable with fractional AUC, implying that the latter procedure could be used as a substitute for the Nelson–Wagner method. A comparison of drug release profiles for the four formulations revealed that in three of the four formulations, in vivo release was slightly faster than that in vitro, but the results were not statistically significant (P > 0.0001). An excellent linear correlation (R2 values between 0.97 and 0.99) was obtained when % in vitro release for each formulation was compared with its corresponding in vivo release profile, obtained by using fraction absorbed (Nelson–Wagner method) or fractional AUC. In summary, using the four formulations that exhibited different release rates, a Level A IVIVC was established using the FDA-recommended deconvolution method and fractional AUC approach. The excellent relationship between in vitro drug release and the amount of drug absorbed in vivo in this study was corroborated by the nearly 1:1 correlation (R2 greater than 0.97) between in vitro release and in vivo performance. Thus, the results of the current study suggest that proper selection of an in vitro method to assess drug release from long-acting injectables will aid in obtaining a Level A IVIVC.

Albumin‐Assisted Method Allows Assessment of Release of Hydrophobic Drugs From Nanocarriers

“…Among the in vitro release methods developed so far, the sample‐and‐separate approach is the most widely used, mainly because this methodology is simple and does not require complex apparatus . However, there are certain concerns about this approach, in particular, inability to mimic various in vivo release conditions, loss of the particles during sampling procedure, and poor hydrodynamic conditions .…”

“…Many studies have shown that membrane dialysis approach provides a good correlation with in vivo experiments . However, due to its inability to achieve sink conditions, use of the dialysis approach to analyze the release of hydrophobic drugs can lead to ambiguous interpretations.…”

“…Of these, three most important approaches are: 1) sample‐and‐separate method; 2) membrane dialysis; and 3) flow through approach . None of these methods is flawless, but they have been shown to be relatively accurate providing good in vitro‐in vivo correlation in many cases …”

In vitro-in vivo correlation of parenteral risperidone polymeric microspheres

“…Over the past decades, the development of IVIVCs for parenteral microspheres has increasingly gained more significance. The same principles as detailed in the FDA IVIVC Guidance on extended release oral dosage forms have been applied in literature to develop IVIVCs for parenteral drug products [15][16][17][18][19][20]. However, due to their complex release characteristics (e.g.…”

“…bi-or tri-phasic release profiles), deconvolution of in vivo data and correlation with in vitro release data have been challenging. Until now, there are only a few literature reports on the establishment of IVIVCs for parenteral polymeric microspheres, albeit with different in vitro release testing approaches, such as the USP 4 method [19,20], dialysis based methods [17,18], as well as sample-and-separate methods [21][22][23]. None of these has addressed the importance of developing an IVIVC for compositionally equivalent PLGA microspheres with manufacturing differences.…”