Perfluorodecalin allows resuspension and prevents sediment solidification of extended-release drug formulations in primary packaging

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Abstract

In this technical note we show with two simple experiments how Perfluorodecalin (PFD), an injectable perfluorocarbon, can be used as an agent for resuspending microparticulate suspensions in primary packaging containers for injection. Furthermore, we explain how this can be a substantial improvement regarding patient compliance in comparison to the commonly used gas headspace for resuspension. Our experiments are conducted with poly(lactic-co-glycolic acid) particles (often used in extended-release pharmaceutical formulations for injection) and in primary packaging that is commonly used in injection devices (glass cartridges). The results show that our method is feasible for resuspension and moreover even sediment solidification/caking is reduced. The differences between the two datasets collected are statistically significant with p < 0.01 in both cases.

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Review of hybrid PLGA nanoparticles: Future of smart drug delivery and theranostics medicine

Jana Ghitman, Elena Bîru, Raluca Stan … (2020)

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Understanding the fundamentals of perfluorocarbons and perfluorocarbon emulsions relevant to in vivo oxygen delivery.

Jean G Riess (2005)

The unique behavior of perfluorocarbons (PFCs), including their high oxygen dissolving capacity, hydrophobic and lipophobic character, and extreme inertness, derive directly, in a predictable manner, from the electronic structure and spatial requirements of the fluorine atom. Their low water solubility is key to the prolonged in vivo persistence of the now commercially available injectable microbubbles that serve as contrast agents for diagnostic ultrasound imaging. Oxygent, a stable, small-sized emulsion of a slightly lipophilic, rapidly excreted PFC, perfluorooctyl bromide (perflubron), has been engineered. Significant oxygen delivery has been established in animal models and through Phase II and III human clinical trials. However, an inappropriate testing protocol and the lack of funding led to temporary suspension of the trials.

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Pharmacokinetics and side effects of perfluorocarbon-based blood substitutes.

S Flaim (1993)

Perfluorochemicals are fluorine-saturated carbon-based molecules which demonstrate utility in the areas of imaging and oxygen delivery. In general, these molecules are biologically inert and, therefore, do not pose toxicologic risk from metabolic degradation. Intravenous (i.v.) perfluorocarbon (PFC) emulsions are cleared from the blood through a process involving phagocytosis of emulsion particles by reticuloendothelial macrophages (RES) and ultimate elimination through the lung in expired air. RES phagocytosis of PFC emulsion particles leads to characteristic, predictable, and reversible biological effects that are a consequence of a normal host-defense mechanism. This mechanism is characterized by dose-related stimulation of macrophages and subsequent release of intracellular products (particularly metabolites of the arachidonic acid cascade and cytokines) which are responsible for most of the biological effects associated with i.v. PFC emulsions (i.e., cutaneous flushing and fever at lower doses, and macrophage hypertrophy and recruitment at higher doses). These biological effects are reversible, and do not result in any permanent tissue alteration, even with prolonged exposure at relatively high doses. The rate of PFC elimination from the RES is proportional to the vapor pressure of the PFC, inversely proportional to molecular weight and positively influenced by lipophilicity. This dose-dependent respiratory excretion occurs with no evidence of metabolic products. Repeated administration of high doses of PFC emulsion may lead to a saturation of the RES-mediated clearance capacity, resulting in a redistribution of PFC to non-RES tissues and ingestion by resident or mobile macrophages. This condition is benign with respect to the integrity of the surrounding parenchyma, as well as to the macrophages themselves. Increased pulmonary residual volume (IPRV) due to pulmonary gas (air) trapping, a reversible side effect, has been observed with i.v. doses of PFC emulsion in some animal species. The gross morphological change associated with IPRV is not accompanied by any histological alteration other than the appearance of vacuolated macrophages (characteristic of the normal clearance mechanism) and some minor, increased interalveolar cellularity. Animal lungs affected by IPRV have a normal, pale pink appearance with no visible lesions or signs of edema. The degree of IPRV is dependent on species, PFC dose, and type of PFC administered; PFCs with higher vapor pressures produce the most severe cases of IPRV in sensitive species. Species sensitivity depends upon physiological and morphological characteristics. There is no evidence indicating that IPRV occurs in humans. Although i.v. PFC emulsions may elicit minor untoward effects, these effects are reversible and, at clinically relevant doses, do not pose a toxicologic risk.

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Author and article information

Contributors

Daniel Primavessy:

ORCID: http://orcid.org/0000-0002-3569-5231

daniel.primavessy@midas-pharma.com

Journal

Journal ID (nlm-ta): Drug Deliv Transl Res

Journal ID (iso-abbrev): Drug Deliv Transl Res

Title: Drug Delivery and Translational Research

Publisher: Springer US (New York )

ISSN (Print): 2190-393X

ISSN (Electronic): 2190-3948

Publication date (Electronic): 4 May 2024

Publication date PMC-release: 4 May 2024

Publication date (Print): 2025

Volume: 15

Issue: 1

Pages: 1-6

Affiliations

[1 ]Midas Pharma GmbH, Rheinstrasse 49, 55218 Ingelheim am Rhein, Germany

[2 ]EDUMO Consulting, Professor-Neeb-Strasse 4, 55291 Saulheim, Germany

[3 ]Institute of Organismic and Molecular Evolution, Johannes Gutenberg Universität Mainz, J. J. Becher-Weg 30A, ( https://ror.org/023b0x485) 55128 Mainz, Germany

Author information

Daniel Primavessy http://orcid.org/0000-0002-3569-5231

Sarah Büttner http://orcid.org/0000-0003-1168-4682

Sigrid Saaler-Reinhardt http://orcid.org/0009-0007-1457-6886

Article

Publisher ID: 1598

DOI: 10.1007/s13346-024-01598-7

PMC ID: 11614965

PubMed ID: 38704495

SO-VID: 4e8f341e-a91b-43a5-868a-835a9bc11da9

License:

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