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. 2023 Oct 19:3:1270584.
doi: 10.3389/fddev.2023.1270584. eCollection 2023.

Development of a depot formulation with an in situ non-lamellar liquid crystal-forming system with phospholipids

Hiroaki Todo  1 , Rina Niki  1 , Akie Okada  1 , Ibuki Narita  1 , Kazuya Inamura  1 , Ayu Ito  1 , Shoko Itakura  1 , Ichiro Hijikuro  2 , Kenji Sugibayashi  1   3
Affiliations

Development of a depot formulation with an in situ non-lamellar liquid crystal-forming system with phospholipids

Hiroaki Todo et al. Front Drug Deliv. .

Abstract

Non-lamellar liquid crystal (NLLC) structures have gained increasing attention for the controlled release of entrapped drugs. In the present study, an in situ NLLC structure-forming depot formulation through contact with water was developed using a ternary mixture system of soya phosphatidyl choline (SPC), 1, 2-dioleoyl-sn-glycero-3-phosphoglycerol sodium salt (DOPG), and sorbitan trioleate (Span 85), and the long-term release of an entrapped model drug, leuprolide acetate (LA), was investigated using evaluation of in vitro release and in vivo blood concentration-time profiles. Polarized images and small angle X-ray scattering analysis were used to confirm the presence of NLLC structures by contacting the prepared formulation with water. In addition, LA release and blood concentration-time profiles were investigated using in vitro and in vivo experiments, respectively. In situ NLLC constructed formulations by contacting water were achieved using a ternary mixture of SPC, DOPG, and Span 85. In particular, negative curvature was increased with an increase in the amount of Span 85 in the formulation, and an Fd3m structure was obtained with a sustained release of LA. A maintained blood concentration of LA over 21 days was confirmed by subcutaneous (s.c.) administration of the formulation. No retained administered formulation at the injection site was confirmed 28 days after administration without any signs of irritation, inflammation, or other apparent toxicity confirmed by visual observation. This result may be helpful for the development of a lipid-based formulation of peptides and proteins with sustained drug release.

Keywords: in situ forming system; lipid-based depot formulation; long-acting drug delivery system; non-lamellar liquid crystal; sustained release.

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Conflict of interest statement

Author IH was employed by Farnex Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Polarized images of prepared formulations after mixing with water.
FIGURE 2
FIGURE 2
Structural analysis of the formulations after contacting water using small angle X-ray scattering analysis.
FIGURE 3
FIGURE 3
LA release profile from formulations over 7 days. (A): release profile from F85:5:10 (○), F75:15:10 ( ), F65:25:10 (△), and F55:35:10 (◇), (B): release profile from F55:5:40 (●), F45:15:40 (■), and F35:25:40 (▲), (C): release profile from F70:5:25 (●), F60:15:25 (■), and F50:25:25 (▲). Each value shows the mean ± S.D. (n = 3).
FIGURE 4
FIGURE 4
Plasma LA concentration–time profile over 21 days after subcutaneous injection of LA solution ( ), F65:25:10 (△), F55:35:10 (◇), and F55:5:40 (●). Each point shows the mean ± S.E. (n = 3–5). **p < 0.001 LA solution vs. the other formulations at 0.04 h, *p < 0.05 F55:5:40 vs. F65:25:10 and F55:35:10 at 1 day.
FIGURE 5
FIGURE 5
Evaluation of injectability force of F65:25:10, F55:35:10, and F55:5:40. The injectability force of the formulation was performed with 23G. Each value shows the mean ± S.D. (n = 3).
FIGURE 6
FIGURE 6
Remaining formulation at the injection site at 7 and 28 days after s.c. administration. (A–C) show 7 days after administration of (A) F55:5:40, (B) F55:35:10, and (C) F65:25:10, respectively. (D,E) show 28 days after administration of F55:35:10 and F65:25:10, respectively.
See this image and copyright information in PMC

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