Solid Lipid Particles for Oral Delivery of Peptide and Protein Drugs II – The Digestion of Trilaurin Protects Desmopressin from Proteolytic Degradation

Christophersen, Philip C.; Zhang, Long; Müllertz, Anette; Nielsen, Hanne Mørck; Yang, Mingshi; Mu, Huiling

doi:10.1007/s11095-014-1337-z

Cited by 40 publications

(22 citation statements)

References 25 publications

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“…Desmopressin was chosen as a model peptide drug to enable future in vivo experiments, as it can be absorbed orally although to a limited extent. The presence of trilaurin (TG12) particles in the biorelevant medium was found to accelerate the release of desmopressin from solid lipid microparticles (SLM), as well as reduce the degradation of desmopressin by protease (10). Significant protection of desmopressin from proteolytic degradation has also been observed previously in the presence of a short chain (C6) monoglyceride (11).…”

Section: Introductionmentioning

confidence: 59%

“…SLM were prepared and loaded with desmopressin using the method described previously (10). In short, desmopressin in aqueous solution (50 mg/mL) was incorporated in lipid matrices consisting of TG14, TG16, and TG18, respectively.…”

Section: Preparation Of Slmmentioning

confidence: 99%

“…In recent studies, the authors described an in vitro lipolysis model capable of assessing the release and degradation of peptides and proteins from solid lipid particles (9,10). Desmopressin was chosen as a model peptide drug to enable future in vivo experiments, as it can be absorbed orally although to a limited extent.…”

Section: Introductionmentioning

confidence: 99%

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Solid Lipid Particles for Oral Delivery of Peptide and Protein Drugs III — the Effect of Fed State Conditions on the In Vitro Release and Degradation of Desmopressin

Christophersen

Vaghela

Müllertz

et al. 2014

AAPS J

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The effect of food intake on the release and degradation of peptide drugs from solid lipid particles is unknown and was therefore investigated in vitro using different fed state media in a lipolysis model. Desmopressin was used as a model peptide and incorporated into solid lipid particles consisting of trimyristin (TG14), tripalmitin (TG16), and tristearin (TG18), respectively. Fasted state and fed state media with varying phospholipid and bile salt concentrations, as well as fed state media with milk and oleic acid glycerides, respectively, were used as the release media. The presence of oleic acid glycerides accelerated the release of desmopressin significantly from all solid lipid particles both in the presence and absence of lipase. The presence of oleic acid glycerides also reduced the degradation rate of desmopressin, probably due to the interactions between the lipids and the protease or desmopressin. Addition of a medium chain triglyceride, trilaurin, in combination with drug-loaded lipid particles diminished the food effect on the TG18 particles, and trilaurin is therefore proposed to be a suitable excipient for reduction of the food effect. Overall, the present study shows that strategies to reduce food effect, such as adding trilaurin, for lipid particle formulations should be considered as drug release from such formulations might be influenced by the presence of food in the gastrointestinal tract.

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Section: Introductionmentioning

confidence: 59%

Section: Preparation Of Slmmentioning

confidence: 99%

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Solid Lipid Particles for Oral Delivery of Peptide and Protein Drugs III — the Effect of Fed State Conditions on the In Vitro Release and Degradation of Desmopressin

Christophersen

Vaghela

Müllertz

et al. 2014

AAPS J

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“…However, it is readily degraded by a-chymotrypsin (Kahns et al, 1993;Fredholt et al, 1999;Christophersen et al, 2014). The degradation of desmopressin acetate, DES/AOT-SEDDS-F15 and DES/AOT-SEDDS-F4 are presented in Figure 7.…”

Section: Enzymatic Stability Studiesmentioning

confidence: 99%

“…Consequently, the oral bioavailability of the above mentioned formulations is less than 1% (Kahns et al, 1993;Ilan et al, 1996;Fredholt et al, 1999;Wang et al, 2015). Thus, several attempts to develop alternative oral delivery systems such as mucoadhesive submicron emulsions (Ilan et al, 1996), solid lipid particles (Christophersen et al, 2014) as well as prodrugs (Kahns et al, 1993;Wang et al, 1999Wang et al, , 2002 have been undertaken to increase its bioavailability.…”

Section: Introductionmentioning

confidence: 99%

Development andin vitroevaluation of an oral SEDDS for desmopressin

et al. 2016

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Context: Self-emulsifying drug delivery systems (SEDDS) are among most promising tools for improving oral peptide bioavailability. Objective: In this study, in vitro protective effect of SEDDS containing desmopressin against presystemic inactivation by glutathione and a-chymotrypsin was evaluated. Materials and methods: The partitioning coefficient (log P) of desmopressin was increased via hydrophobic ion pairing using anionic surfactants. Solubility studies were performed to select the appropriate solvents for SEDDS preparation. Subsequently, droplet size and emulsification properties of 22 SEDDS formulations were evaluated. Moreover, the peptide-surfactant complex was dissolved in two chosen SEDDS formulations. Finally, SEDDS containing desmopressin were characterized regarding lipase stability, toxicity, and in vitro protective effect toward glutathione and a-chymotrypsin. Results: Desmopressin log P was increased from initial À6.13 to 0.33 using sodium docusate. The resulting desmopressin docusate complex (DES/AOT) was incorporated in two different SEDDS formulations, containing Capmul 907 P as main solvent. DES/AOT-SEDDS-F4 (containing 0.07% w/w DES/AOT) was composed of 50% Capmul 907P, 40% Cremophor RH40, and 10% Transcutol. The comparatively more hydrophilic formulation DES/AOT-SEDDS-F15 (containing 0.25% w/w DES/AOT) consisted of 20% Capmul 907P, 40% Acconon MC8-2, and 40% Tween 20. Both formulations were stable toward digestion by lipase and protected desmopressin toward a-chymotrypsin degradation. Moreover, DES/AOT-SEDDS-F4 also protected the peptide from thiol/disulfide exchange reactions with glutathione and was not cytotoxic at a concentration of 0.375% (w/w). Conclusion: DES/AOT-SEDDS-F4 protected desmopressin from in vitro glutathione and a-chymotrypsin degradation. DES/AOT-SEDDS-F4 was metabolically stable and nontoxic. Therefore, it could be considered as a potential delivery system for oral desmopressin administration.

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Lipid Nanoparticles: Versatile Drug Delivery Vehicles for Traversing the Blood Brain Barrier to Treat Brain Cancer

Cai,

Drummond,

Zhai

et al. 2024

Adv Funct Materials

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The blood‐brain barrier (BBB) poses a significant challenge in delivering therapeutic agents for brain diseases due to its high selectivity against foreign substances. This limitation greatly hampers the effectiveness of conventional chemotherapeutic drugs in treating brain cancers. In response, lipid‐based nanoparticles (LNPs) have emerged as a promising approach, offering opportunities for targeted drug delivery by conjugating targeting ligands onto their surface. This review provides a comprehensive overview of recent advancements in utilizing LNPs to traverse the BBB for enhanced transport of bioactive compounds into the brain, specifically for cancer treatments. Beginning with an exploration of the biological structure and functions of the BBB and the blood‐brain tumor barrier (BBTB), the review highlights the advantages presented by LNPs. Subsequently, it delves into strategies for surface modification of nanoparticles to enhance BBB targeting and improve efficacy in brain cancer treatment. Finally, the review offers insights into future prospects for designing the next generation of LNPs. The review presented herein aims to contribute to the ongoing efforts in overcoming the challenges associated with BBB penetration, ultimately advancing therapeutic strategies for brain cancer and other neurological disorders.

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Solid Lipid Particles for Oral Delivery of Peptide and Protein Drugs II – The Digestion of Trilaurin Protects Desmopressin from Proteolytic Degradation

Abstract: TG12 is a very interesting lipid for oral lipid formulations containing peptides and proteins as it alters release and degradation of the incorporated desmopressin. The present study demonstrates the possibility of bio-relevant in vitro evaluation of lipid-based solid particles.

Cited by 40 publications

References 25 publications

Solid Lipid Particles for Oral Delivery of Peptide and Protein Drugs III — the Effect of Fed State Conditions on the In Vitro Release and Degradation of Desmopressin

Solid Lipid Particles for Oral Delivery of Peptide and Protein Drugs III — the Effect of Fed State Conditions on the In Vitro Release and Degradation of Desmopressin

Development andin vitroevaluation of an oral SEDDS for desmopressin

Lipid Nanoparticles: Versatile Drug Delivery Vehicles for Traversing the Blood Brain Barrier to Treat Brain Cancer

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