Development of a bio-relevant in vitro release testing method for subcutaneous and intramuscular oil depot formulations

Jesper Østergaard; Nina Mertz; Valeria Gancho; Angelina Le; Marc Barber; Padmavani Bezawada; Susan Weng Larsen; Matthew N. O'Brien Laramy; Jaini Rohit

doi:10.1016/j.jddst.2024.106412

Development of a bio-relevant in vitro release testing method for subcutaneous and intramuscular oil depot formulations

Jesper Østergaard^*, Nina Mertz, Valeria Gancho, Angelina Le, Marc Barber, Padmavani Bezawada, Susan Weng Larsen, Matthew N. O'Brien Laramy, Jaini Rohit^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

Oil depot formulations constitute a class of long-acting injectables with clinical and commercial precedence used to prolong exposure for hydrophobic compounds. The development of long-acting injectable formulations can be guided by the use of in vitro release testing methods that simulate in vivo drug release under bio-relevant conditions. However, the development of such methods for oil depot formulations has been limited. This study presents a single-use in vitro release (IVR) cartridge holding a size exclusion chromatography (SEC) matrix for emulating subcutaneous or intra-muscular tissue. Utilizing rat in vivo data from literature as guidance, the aim was to explore development of an in vitro drug release testing approach for injectable oil depot formulations. Release of p-hydroxyazobenzene (PHAB) was investigated upon injection of oil solutions into the IVR cartridge followed by intermittent elution with 1 mL release medium by gravity flow. The in vitro release profiles were described by first-order kinetics and consistent with previously published in vivo release observations. Bovine serum albumin solution was the preferred release medium since it provided higher release rates than sodium dodecyl sulfate solutions. In contrast to in vivo studies, the in vitro PHAB release from sesame oil was concentration-dependent as a decreasing PHAB fraction may be bound to albumin at increasing PHAB concentrations (range 1–20 mg/mL). The SEC matrix confined the oil solution at the injection site; leading to a decreasing PHAB release rate with increasing injection volume similar to the in vivo situation. In vitro release of PHAB decreased with increasing oil-buffer distribution coefficients, exhibiting similar ranking as was observed in vivo in rats. The in vitro release cartridge used in this study was able to capture in vivo release observed for subcutaneously and intramuscularly injected oily PHAB solutions in rats and holds promise as an in vitro release testing approach for injectable depots.

Original language	English
Article number	106412
Journal	Journal of Drug Delivery Science and Technology
Volume	102
Number of pages	11
ISSN	1773-2247
DOIs	https://doi.org/10.1016/j.jddst.2024.106412
Publication status	Published - 2024

Bibliographical note

Funding Information:
This research was supported by Pfizer Inc.The authors would like to thank Rita Wulff Rasmussen (University of Copenhagen) for excellent technical assistance and Suman Luthra (Pfizer Inc.) for support in the initial project phase. J\u00D8 acknowledges Pfizer Inc. for financial support. J\u00D8 would like to thank Mogens \u00D8stergaard for providing access to workshop and manufacturing of IVR cartridge manifolds.

Publisher Copyright:
© 2024 The Authors

Keywords

In vitro in vivo correlation
In vitro release testing
Intra-muscular administration
Long-acting injectable
Oil depot formulation
Subcutaneous administration

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Development of a bio-relevant in vitro release testing method for subcutaneous and intramuscular oil depot formulations. / Østergaard, Jesper ; Mertz, Nina; Gancho, Valeria; Le, Angelina; Barber, Marc; Bezawada, Padmavani; Larsen, Susan Weng; O'Brien Laramy, Matthew N.; Rohit, Jaini.

In: Journal of Drug Delivery Science and Technology, Vol. 102, 106412, 2024.

Research output: Contribution to journal › Journal article › Research › peer-review

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abstract = "Oil depot formulations constitute a class of long-acting injectables with clinical and commercial precedence used to prolong exposure for hydrophobic compounds. The development of long-acting injectable formulations can be guided by the use of in vitro release testing methods that simulate in vivo drug release under bio-relevant conditions. However, the development of such methods for oil depot formulations has been limited. This study presents a single-use in vitro release (IVR) cartridge holding a size exclusion chromatography (SEC) matrix for emulating subcutaneous or intra-muscular tissue. Utilizing rat in vivo data from literature as guidance, the aim was to explore development of an in vitro drug release testing approach for injectable oil depot formulations. Release of p-hydroxyazobenzene (PHAB) was investigated upon injection of oil solutions into the IVR cartridge followed by intermittent elution with 1 mL release medium by gravity flow. The in vitro release profiles were described by first-order kinetics and consistent with previously published in vivo release observations. Bovine serum albumin solution was the preferred release medium since it provided higher release rates than sodium dodecyl sulfate solutions. In contrast to in vivo studies, the in vitro PHAB release from sesame oil was concentration-dependent as a decreasing PHAB fraction may be bound to albumin at increasing PHAB concentrations (range 1–20 mg/mL). The SEC matrix confined the oil solution at the injection site; leading to a decreasing PHAB release rate with increasing injection volume similar to the in vivo situation. In vitro release of PHAB decreased with increasing oil-buffer distribution coefficients, exhibiting similar ranking as was observed in vivo in rats. The in vitro release cartridge used in this study was able to capture in vivo release observed for subcutaneously and intramuscularly injected oily PHAB solutions in rats and holds promise as an in vitro release testing approach for injectable depots.",

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note = "Funding Information: This research was supported by Pfizer Inc.The authors would like to thank Rita Wulff Rasmussen (University of Copenhagen) for excellent technical assistance and Suman Luthra (Pfizer Inc.) for support in the initial project phase. J\u00D8 acknowledges Pfizer Inc. for financial support. J\u00D8 would like to thank Mogens \u00D8stergaard for providing access to workshop and manufacturing of IVR cartridge manifolds. Publisher Copyright: {\textcopyright} 2024 The Authors",

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AU - Østergaard, Jesper

AU - Mertz, Nina

AU - Gancho, Valeria

AU - Le, Angelina

AU - Barber, Marc

AU - Bezawada, Padmavani

AU - Larsen, Susan Weng

AU - O'Brien Laramy, Matthew N.

AU - Rohit, Jaini

N1 - Funding Information: This research was supported by Pfizer Inc.The authors would like to thank Rita Wulff Rasmussen (University of Copenhagen) for excellent technical assistance and Suman Luthra (Pfizer Inc.) for support in the initial project phase. J\u00D8 acknowledges Pfizer Inc. for financial support. J\u00D8 would like to thank Mogens \u00D8stergaard for providing access to workshop and manufacturing of IVR cartridge manifolds. Publisher Copyright: © 2024 The Authors

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N2 - Oil depot formulations constitute a class of long-acting injectables with clinical and commercial precedence used to prolong exposure for hydrophobic compounds. The development of long-acting injectable formulations can be guided by the use of in vitro release testing methods that simulate in vivo drug release under bio-relevant conditions. However, the development of such methods for oil depot formulations has been limited. This study presents a single-use in vitro release (IVR) cartridge holding a size exclusion chromatography (SEC) matrix for emulating subcutaneous or intra-muscular tissue. Utilizing rat in vivo data from literature as guidance, the aim was to explore development of an in vitro drug release testing approach for injectable oil depot formulations. Release of p-hydroxyazobenzene (PHAB) was investigated upon injection of oil solutions into the IVR cartridge followed by intermittent elution with 1 mL release medium by gravity flow. The in vitro release profiles were described by first-order kinetics and consistent with previously published in vivo release observations. Bovine serum albumin solution was the preferred release medium since it provided higher release rates than sodium dodecyl sulfate solutions. In contrast to in vivo studies, the in vitro PHAB release from sesame oil was concentration-dependent as a decreasing PHAB fraction may be bound to albumin at increasing PHAB concentrations (range 1–20 mg/mL). The SEC matrix confined the oil solution at the injection site; leading to a decreasing PHAB release rate with increasing injection volume similar to the in vivo situation. In vitro release of PHAB decreased with increasing oil-buffer distribution coefficients, exhibiting similar ranking as was observed in vivo in rats. The in vitro release cartridge used in this study was able to capture in vivo release observed for subcutaneously and intramuscularly injected oily PHAB solutions in rats and holds promise as an in vitro release testing approach for injectable depots.

AB - Oil depot formulations constitute a class of long-acting injectables with clinical and commercial precedence used to prolong exposure for hydrophobic compounds. The development of long-acting injectable formulations can be guided by the use of in vitro release testing methods that simulate in vivo drug release under bio-relevant conditions. However, the development of such methods for oil depot formulations has been limited. This study presents a single-use in vitro release (IVR) cartridge holding a size exclusion chromatography (SEC) matrix for emulating subcutaneous or intra-muscular tissue. Utilizing rat in vivo data from literature as guidance, the aim was to explore development of an in vitro drug release testing approach for injectable oil depot formulations. Release of p-hydroxyazobenzene (PHAB) was investigated upon injection of oil solutions into the IVR cartridge followed by intermittent elution with 1 mL release medium by gravity flow. The in vitro release profiles were described by first-order kinetics and consistent with previously published in vivo release observations. Bovine serum albumin solution was the preferred release medium since it provided higher release rates than sodium dodecyl sulfate solutions. In contrast to in vivo studies, the in vitro PHAB release from sesame oil was concentration-dependent as a decreasing PHAB fraction may be bound to albumin at increasing PHAB concentrations (range 1–20 mg/mL). The SEC matrix confined the oil solution at the injection site; leading to a decreasing PHAB release rate with increasing injection volume similar to the in vivo situation. In vitro release of PHAB decreased with increasing oil-buffer distribution coefficients, exhibiting similar ranking as was observed in vivo in rats. The in vitro release cartridge used in this study was able to capture in vivo release observed for subcutaneously and intramuscularly injected oily PHAB solutions in rats and holds promise as an in vitro release testing approach for injectable depots.

KW - In vitro in vivo correlation

KW - In vitro release testing

KW - Intra-muscular administration

KW - Long-acting injectable

KW - Oil depot formulation

KW - Subcutaneous administration

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DO - 10.1016/j.jddst.2024.106412

M3 - Journal article

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JO - Journal of Drug Delivery Science and Technology

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