A liposomal formulation for the oral application of the investigational hepatitis B drug Myrcludex B

Uhl, Philipp; Helm, Frieder; Hofhaus, Götz; Brings, Sebastian; Kaufman, Christina L.; Leotta, Karin; Urban, Stephan; Haberkorn, Uwe; Mier, Walter; Fricker, Gert

doi:10.1016/j.ejpb.2016.03.031

Cited by 66 publications

(58 citation statements)

References 33 publications

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“…It is critical to accurately characterize liposomes and drug-liposome interactions as biophysical properties of liposomes are known to influence biological activity, biodistribution, and toxicity. Among the available techniques (Dynamic Light Scattering (DLS), Size Exclusion Chromatography (SEC), Atomic Force Microscopy (AFM), and cryo-EM), cryo-EM is the most precise and direct method to determine liposome lamellarity, size, shape and ultrastructure, which may reveal clues to mechanism of action toward the clinical endpoints of efficacy and toxicity (Aissaoui et al, 2011;Al-Ahmady et al, 2016;Baxa, 2018;Bonnaud et al, 2013;Crawford et al, 2011;De Carlo et al, 2004;Lepault et al, 1985;Uhl et al, 2017;Uhl et al, 2016;Zhang et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Cryo-EM sample preparation method for extremely low concentration liposomes

Tonggu

Wang

2018

Preprint

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Liposomes are widely used as delivery systems in pharmaceutical, cosmetics and food industries, as well as a system for structural and functional study of membrane proteins. To accurately characterize liposomes, cryo-Electron Microscopy (cryo-EM) has been employed as it is the most precise and direct method to determine liposome lamellarity, size, shape and ultrastructure. However, its use is limited by the number of liposomes that can be trapped in the thin layer of ice that spans holes in the perforated carbon film on EM grids. We report a long-incubation method for increasing the density of liposomes in holes. By increasing the incubation time, high liposome density was achieved even with extremely dilute (in the nanomolar range) liposome solutions. This long-incubation method has been successfully employed to study the structure of an ion channel reconstituted into liposomes. This method will also be useful for preparing other biological macromolecules / assemblies for structural studies using cryo-EM.

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Section: Introductionmentioning

confidence: 99%

Cryo-EM sample preparation method for extremely low concentration liposomes

Tonggu

Wang

2018

Preprint

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“…Li et al (2010), J. Parmentier et al (2011bParmentier et al ( , 2014 and P. Uhl et al (2016) and will be discussed in this section. Results for the best performing formulations are summarized in Table 2.…”

Section: In Vivo Investigation Of Liposomes Containing Archaeal Lipidmentioning

confidence: 99%

“…Generally, the investigated mixed vesicles and archaeosomes were prepared as described in Section 3.2. The formulations were administered by oral gavage to male rats, male Wistar rats or mice with induced diabetes, respectively (Li et al, 2010;Parmentier et al, 2014;Parmentier et al, 2011b;Uhl et al, 2016).…”

Section: In Vivo Investigation Of Liposomes Containing Archaeal Lipidmentioning

confidence: 99%

“…Additionally, cetylpyridinium chloride (CpCl) was used as permeation enhancer (Parmentier et al, 2014), which also is likely to play a role in the large increase in hGH bioavailability. When considering the potentially beneficial effect of the permeation enhancer CpCl and the pretreatment with omeprazole, contradictory results were achieved in a recent study by P. Uhl et al (2016). Here the performance of mixed vesicles containing GCTE for the oral administration of the investigational drug Myrcludex B was compared to conventional liposomes and free drug.…”

Section: In Vivo Investigation Of Liposomes Containing Archaeal Lipidmentioning

confidence: 99%

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Archaeal lipids in oral delivery of therapeutic peptides

Jacobsen

Jensen

Fricker

et al. 2017

European Journal of Pharmaceutical Sciences

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Archaea contain membrane lipids that differ from those found in the other domains of life (Eukarya and Bacteria). These lipids consist of isoprenoid chains attached via ether bonds to the glycerol carbons at the sn-2,3 positions. Two types of ether lipids are known, polar diether lipids and bipolar tetraether lipids. The inherent chemical stability and unique membrane-spanning characteristics of tetraether lipids render them interesting for oral drug delivery purposes. Archaeal lipids form liposomes spontaneously (archaeosomes) and may be incorporated in conventional liposomes (mixed vesicles). Both types of liposomes are promising to protect their drug cargo, such as therapeutic peptides, against the acidic environment of the stomach and proteolytic degradation in the intestine. They appear to withstand lipolytic enzymes and bile salts and may thus deliver orally administered therapeutic peptides to distant sections of the intestine or to the colon, where they may be absorbed, eventually by the help of absorption enhancers. Archaeal lipids and their semisynthetic derivatives may thus serve as biological source for the next generation oral drug delivery systems. The aim of this review is to present a systematic overview over existing literature on archaea carrying diether and tetraether lipids, lipid diversity, means of lipid extraction and purification, preparation and in vitro stability studies of archaeal lipid-based liposomal drug carriers and in vivo proof-of concepts studies.

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“…Moreover, the majority of the publications concern the entrapment of heat labile peptides and proteins. These proteins and peptides have been entrapped into VPGs and liposomes for different routes of administration: oral [21,30,31], nasal [33], and iv injection [17,20,28,29], or as VPG-depot formulations [13,34,48]. Various organs were targeted as therapeutic sites: cancerous tissue [10,26,35], the central nervous system (CNS) and brain [28,32,33], liver [31], and skin [18,19].…”

Section: Dual Centrifugation: Current Application In Liposome Researchmentioning

confidence: 99%

Dual Centrifugation - A Novel “in-vial” Liposome Processing Technique

Massing¹,

Ingebrigtsen²,

Škalko‐Basnet³

et al. 2017

Liposomes

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Conventional liposome preparation methods bear many limitations, such as poor entrapment efficiencies for hydrophilic drugs, batch size limitations, and limited options for aseptic manufacturing. Liposome preparation by dual centrifugation (DC) is able to overcome most of these limitations. DC differs from normal centrifugation by an additional rotation of the samples during the centrifugation process. Thus, the direction of the centrifugal forces changes continuously in the sample vials. The consequential powerful sample movements inside the vials result in powerful homogenization of the sample. Since this "in-vial" homogenization is optimal for viscous samples, semisolid "vesicular phospholipid gels" (VPGs) are preferred intermediates in the liposome manufacturing by DC. The DC method easily enables aseptic preparation and is gentler as compared to other methods, such as high-pressure homogenization. The method allows very small samples to be prepared, and VPG batches down to 1-5 mg scale have been prepared successfully. VPGs have several applications; they are attractive as depot formulations, or as stable storage intermediates, and can be easily transferred into conventional liposomal formulations by simple dilution. Here, we aim to present the novel DC-liposome technique; the concept, advantages, and limitations; and provide an overview of the experiences of liposome preparation by DC so far.

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A liposomal formulation for the oral application of the investigational hepatitis B drug Myrcludex B

Cited by 66 publications

References 33 publications

Cryo-EM sample preparation method for extremely low concentration liposomes

Cryo-EM sample preparation method for extremely low concentration liposomes

Archaeal lipids in oral delivery of therapeutic peptides

Dual Centrifugation - A Novel “in-vial” Liposome Processing Technique

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