Self-emulsifying drug delivery systems (SEDDS) disrupt the gut microbiota and trigger an intestinal inflammatory response in rats

Subramaniam, Santhni; Elz, Aurelia; Wignall, Anthony; Kamath, Srinivas; Ariaee, Amin; Hunter, Alexander; Newblack, Tahlia; Wardill, Hannah R.; Prestidge, Clive A.; Joyce, Paul

doi:10.1016/j.ijpharm.2023.123614

Cited by 10 publications

(6 citation statements)

References 57 publications

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“…Regarding polymeric NPs, natural polymers should be used as potential alternatives to synthetic polymers to increase biocompatibility. Several studies report the toxicity of SEDDS, and their disruptive action on intestinal microbiota, which is correlated with the increased expression of proinflammatory cytokines, the reduction in plasma citrulline levels, and the reduction in the mucosal barrier integrity [ 350 ]. In this regard, Naimi et al (2021) underlined the negative impact of some synthetic emulsifiers on the composition and function of intestinal microbiota, with pro-inflammatory molecule production and the consequent increase in intestinal inflammatory syndrome [ 351 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting the Gut: A Systematic Review of Specific Drug Nanocarriers

Garbati,

Picco,

Magrassi

et al. 2024

Pharmaceutics

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The intestine is essential for the modulation of nutrient absorption and the removal of waste. Gut pathologies, such as cancer, inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), and celiac disease, which extensively impact gut functions, are thus critical for human health. Targeted drug delivery is essential to tackle these diseases, improve therapy efficacy, and minimize side effects. Recent strategies have taken advantage of both active and passive nanocarriers, which are designed to protect the drug until it reaches the correct delivery site and to modulate drug release via the use of different physical–chemical strategies. In this systematic review, we present a literature overview of the different nanocarriers used for drug delivery in a set of chronic intestinal pathologies, highlighting the rationale behind the controlled release of intestinal therapies. The overall aim is to provide the reader with useful information on the current approaches for gut targeting in novel therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Targeting the Gut: A Systematic Review of Specific Drug Nanocarriers

Garbati,

Picco,

Magrassi

et al. 2024

Pharmaceutics

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“…Intestinal permeability enhancement and damage to the local tissue by surfactant are two correlated phenomena . A recent study has shown that the composition of a SEDDS containing lipid and surfactant has a significant adverse effect on the rat intestinal system . The lipid component of SEDDS disrupts the intestinal microbiota, while the surfactant triggers intestinal barrier injury in a rat model .…”

Section: Introductionmentioning

confidence: 99%

“… 8 A recent study has shown that the composition of a SEDDS containing lipid and surfactant has a significant adverse effect on the rat intestinal system. 9 The lipid component of SEDDS disrupts the intestinal microbiota, while the surfactant triggers intestinal barrier injury in a rat model. 9 Chassaing et al (2015) have studied the effect of dietary emulsifier in a rat model and observed that a low quantity of carboxymethyl cellulose and polysorbate 80 resulted in mild intestinal inflammation and abnormal metabolic syndrome.…”

Section: Introductionmentioning

confidence: 99%

“… 9 The lipid component of SEDDS disrupts the intestinal microbiota, while the surfactant triggers intestinal barrier injury in a rat model. 9 Chassaing et al (2015) have studied the effect of dietary emulsifier in a rat model and observed that a low quantity of carboxymethyl cellulose and polysorbate 80 resulted in mild intestinal inflammation and abnormal metabolic syndrome. 10 Polysorbate or Tween 80 triggers intestinal microbial dysbiosis by reducing microbial diversity in gut, resulting in intestinal inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Lactoferrin Reduces Surfactant Content in the Self-Emulsifying Drug Delivery System

Khairnar,

Jain,

Chatterjee

2024

ACS Omega

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Self-emulsifying drug delivery systems (SEDDSs) can effectively be employed to formulate drugs with poor oral bioavailability due to low aqueous solubility and high first-pass metabolism. High surfactant content is an existing challenge toward the successful application of SEDDS. A SEDDS is developed with lactoferrin, a natural emulsifier to reduce the Tween content of a fenofibrate (FEN) formulation. FEN SEDDS (SEDDS without lactoferrin) and FEN Lf-SEDDS (SEDDS with lactoferrin) were developed with 30% and 21% Tween content, respectively. Both formulations containing Crodamol GTCC as a lipid component were thermodynamically stable. No significant difference was observed in zeta potential (−9.25 to −12.63 mV), drug content (>85%), and percentage transmittance (>99%) between the two formulations. FEN Lf-SEDDS resulted in higher viscosity and larger particle size than FEN SEDDS. Solidified SEDDS with Aerosil 200 significantly improved in vitro drug release from both formulations than pure FEN. However, FEN SEDDS and FEN Lf-SEDDS did not show a significant difference in cumulative percent release or dissolution efficiency at 120 min. It can be concluded that lactoferrin containing SEDDS with 27% lesser synthetic surfactants (Tween 80 and Span 80) can result in similar physicochemical characteristics. Oral pharmacokinetic study of FEN Lf-SEDDS in a rat model resulted in 1.3 and 5.5 times higher relative bioavailability than marketed product and pure drug, respectively. The addition of lactoferrin could substitute synthetic surfactants in self-emulsifying drug delivery systems significantly.

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“…Recent literature has shifted to investigate the impact of pharmaceutical actives such as antipsychotics and associated excipients on the gut microbiota with many reviews such as one by Minichino et al concluding their ability to trigger gut microbial imbalances, referred to as dysbiosis (Cussotto et al, 2019; Kamath et al, 2023; Minichino et al, 2023; Subramaniam, Elz, et al, 2023; Subramaniam, Kamath, et al, 2023). For example, Tomizawa et al analysed 246 stool samples from 40 patients to uncover a dose-dependent generalised decrease in phylogenic, whole-tree and beta diversity indices (all indicative of a dysbiotic gut microbial profile) in patients administered antipsychotics (Tomizawa et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

The atypical antipsychotic lurasidone positively modulates the gut microbiota in rats: A comparative study to olanzapine

Kamath,

Hunter,

Collins

et al. 2024

Preprint

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Background and PurposeAntipsychotics like olanzapine are associated with significant metabolic dysfunction, attributable to gut microbiota dysbiosis. A recent notion that most psychotropics are detrimental to the gut microbiota has arisen from consistent findings of metabolic adverse effects. However, unlike olanzapine, the metabolic effects of lurasidone are conflicting, with most reports observing weight loss rather than gain. Thus, this study investigates the contrasting effects of olanzapine and lurasidone on the gut microbiota to explore the hypothesis of “gut neutrality” for lurasidone exposure.Experimental ApproachUsing a Sprague-Dawley rat model, the impact of olanzapine and lurasidone administration on the gut microbiota was explored. Faecal and blood samples were collected weekly over a 21-day period to analyse changes to the gut microbiota and related metabolic markers.Key ResultsLurasidone triggered no significant weight gain or metabolic alterations, instead positively modulating gut microbiota through increases in mean OTUs (+50 OTUs) and alpha diversity (+0.5 increase in Shannon’s index). This novel finding suggests an underlying mechanism for lurasidone’s metabolic inertia. In contrast, olanzapine triggered a statistically significant decrease in mean OTUs (−75 OTUs) and substantial compositional variation, suggesting a decrease in microbial richness. Microbiota alterations correlated with metabolic dysfunction, evidenced through a statistically significant 30% increase in weight gain, increase in pro-inflammatory cytokine expression, and increase in blood triglycerides and glycaemic levels.Conclusion and ImplicationsThe study challenges the notion that all antipsychotics disrupt the gut microbiota similarly and highlights the potential benefits of gut positive or neutral antipsychotics like lurasidone in managing metabolic side effects. Further research is warranted to validate these findings in humans to guide personalised pharmacological treatment regimens for schizophrenia.Bullet point summary-What is already known:Olanzapine induces weight gain by disrupting the gut microbiome.The impact of lurasidone on the gut microbiome is unknown and weight gaining propensities unclear.-What this study adds:Lurasidone positively modulates gut microbiota through enhancement of microbial diversity and richness.Potential mechanisms underlying lurasidone’s weight and metabolic neutrality are elucidated.-Clinical significance:Gut neutral antipsychotics like lurasidone could be favourable alternatives for patients unable to tolerate olanzapine.Personalised treatment for schizophrenia considering individual sensitivities to metabolic effects is emphasised.

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Self-emulsifying drug delivery systems (SEDDS) disrupt the gut microbiota and trigger an intestinal inflammatory response in rats

Cited by 10 publications

References 57 publications

Targeting the Gut: A Systematic Review of Specific Drug Nanocarriers

Targeting the Gut: A Systematic Review of Specific Drug Nanocarriers

Lactoferrin Reduces Surfactant Content in the Self-Emulsifying Drug Delivery System

The atypical antipsychotic lurasidone positively modulates the gut microbiota in rats: A comparative study to olanzapine

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