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Spontaneous In Situ Formation of Liposomes from Inert Porous Microparticles for Oral Drug Delivery.

ABSTRACT: Despite the wide-spread use of liposomal drug delivery systems, application of these systems for oral purposes is limited due to their large-scale formulation and storage issues. Proliposomes are one of the formulation approaches for achieving solid powders that readily form liposomes upon hydration. In this work, we investigated a dry powder formulation of a model low-soluble drug with phospholipids loaded in porous functionalized calcium carbonate microparticles. We characterized the liposome formation under conditions that mimic the different gastrointestinal stages and studied the factors that influence the dissolution rate of the model drug. The liposomes that formed upon direct contact with the simulated gastric environment had a capacity to directly encapsulate 25% of the drug in situ. The emerged liposomes allowed complete dissolution of the drug within 15 min. We identified a negative correlation between the phospholipid content and the rate of water uptake. This correlation corroborated the results obtained for the rate of dissolution and liposome encapsulation efficiency. This approach allows for the development of solid proliposomal dosage formulations, which can be scaled up with regular processes.

SUBMITTER: Farzan M

PROVIDER: S-EPMC7465306 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Spontaneous In Situ Formation of Liposomes from Inert Porous Microparticles for Oral Drug Delivery.

Farzan Maryam M Québatte Gabriela G Strittmatter Katrin K Hilty Florentine Marianne FM Schoelkopf Joachim J Huwyler Jörg J Puchkov Maxim M

Pharmaceutics 20200815 8

Despite the wide-spread use of liposomal drug delivery systems, application of these systems for oral purposes is limited due to their large-scale formulation and storage issues. Proliposomes are one of the formulation approaches for achieving solid powders that readily form liposomes upon hydration. In this work, we investigated a dry powder formulation of a model low-soluble drug with phospholipids loaded in porous functionalized calcium carbonate microparticles. We characterized the liposome ...[more]

PMID: 32824155

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Project description:Every year, complications during pregnancy affect more than 26 million women. Some of those diseases are associated with significant morbidity and mortality, as is the case of preeclampsia, the main cause of maternal deaths globally. The ability to improve the delivery of drugs to the placenta upon administration to the mother may offer new opportunities in the treatment of diseases of pregnancy. The objective of this study was to develop megalin-targeting liposome nanocarriers for placental drug delivery. Megalin is a transmembrane protein involved in clathrin-mediated endocytic processes, and is expressed in the syncytiotrophoblast (SynT), an epithelial layer at maternal-fetal interface. Targeting megalin thus offers an opportunity for the liposomes to hitchhike into the SynT, thus enriching the concentration of any associated therapeutic cargo in the placental tissue. PEGylated (2 KDa) lipids were modified with gentamicin (GM), a substrate to megalin receptors as we have shown in earlier studies, and used to prepare placental-targeting liposomes. The ability of the targeting liposomes to enhance accumulation of a fluorescence probe was assessed in an in vivo placental model - timed-pregnant Balb/c mice at gestational day (GD) 18.5. The targeting liposomes containing 10 mol% GM-modified lipids increased the accumulation of the conjugated fluorescence probe in the placenta with a total accumulation of 2.8% of the initial dose, which corresponds to a 94 fold increase in accumulation compared to the free probe (p < .0001), and 2-4 fold accumulation compared to the non-targeting control liposomes (p < .0001), as measured by both tissue extraction assay and ex vivo imaging. Furthermore, confocal images of placental SynT cross-sections show a 3-fold increase of the targeting liposomes compared with the non-targeting liposomes. The rate and extent of uptake of a fluorescent probe encapsulated within targeting liposomes was also probed in an in vitro model of the human placental barrier (polarized BeWo monolayers) using flow cytometry. Targeting liposomes containing 5 mol% GM-modified lipids enhanced the uptake of the probe by 1.5 fold compared to the non-targeting control. An increase to 10 mol% of the modified lipid resulted in further enhancement in uptake, which was 2 fold greater compared to control. In a competition assay, inhibition of the megalin receptors resulted in a significant reduction in uptake of the fluorescence probe encapsulated in GM-modified liposomes compared to the uptake without free inhibitor (p < .0001), implicating the involvement of megalin receptor in the internalization of the liposomes. Taken together, these results demonstrate that megalin-targeted liposomes may offer an opportunity to enhance the delivery of therapeutics to the placenta for the treatment of diseases of pregnancy.

Dataset Information

Spontaneous In Situ Formation of Liposomes from Inert Porous Microparticles for Oral Drug Delivery.

Publications

Spontaneous In Situ Formation of Liposomes from Inert Porous Microparticles for Oral Drug Delivery.

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