Self-emulsifying drug delivery systems (SEDDS): In vivo-proof of concept for oral delivery of insulin glargine.

In spite of recent progress made in the field of peptide and protein delivery, oral administration of insulin and similar drugs remains a challenge. In this study, lipophilicity of insulin glargine (IG) was successfully increased via hydrophobic ion pairing (HIP) with sodium octadecyl sulfate to enable incorporation into self-emulsifying drug delivery systems (SEDDS). Two SEDDS formulations (F1: 20% Labrasol®ALF, 30% polysorbate 80, 10% Croduret 50, 20% oleyl alcohol, 20% Maisine® CC; F2: 30% Labrasol®ALF, 20% polysorbate 80, 30% Kolliphor® HS 15, 20% Plurol® oleique CC 497) were developed and loaded with the IG-HIP complex. Further experiments confirmed increased lipophilicity of the complex, achieving LogDSEDDS/release medium values of 2.5 (F1) and 2.4 (F2) and ensuring sufficient amounts of IG within the droplets after dilution. Toxicological assays indicated minor toxicity and no toxicity inherent to the incorporated IG-HIP complex. SEDDS formulations F1 and F2 were administered to rats via oral gavage and resulted in a bioavailability of 0.55% and 0.44%, corresponding to a 7.7-fold and 6.2-fold increased bioavailability, respectively. Thus, incorporation of complexed insulin glargine into SEDDS formulations provides a promising approach to facilitate its oral absorption.

Hydrophobic Ion Pairing of Small Molecules: How to Minimize Premature Drug Release from SEDDS and Reach the Absorption Membrane in Intact Form.

The present work aimed to form hydrophobic ion pairs (HIPs) of a small molecule remaining inside the oily droplets of SEDDS to a high extent. HIPs of ethacridine and various surfactants classified by functional groups of phosphates, sulfates, and sulfonates were formed and precipitation efficiency, log Dn-octanol/water, and solubility in different excipients were investigated. Most lipophilic HIPs were incorporated into SEDDS and evaluated regarding drug release. Docusate HIPs showed the highest increase in lipophilicity with a precipitation efficiency of 100%, a log Dn-octanol/water of 2.66 and a solubility of 132 mg/mL in n-octanol, 123 mg/mL in oleyl alcohol, and 40 mg/mL in medium chain triglycerides. Docusate HIPs were incorporated into three SEDDS of increasing lipophilicity (F1 < F2 < F3) based on medium chain triglycerides, oleyl alcohol, Kolliphor EL, and Tween 80 (F1: 1 + 5 + 2 + 2; F2: 3 + 3 + 2 + 2; F3: 5 + 1 + 4 + 0). Highest achievable payloads ranged from 74.49 mg/mL (F3) to 97.13 mg/mL (F1) and log DSEDDS/RM increased by at least 7.5 units (4.99, F1). Drug release studies via the diffusion membrane method confirmed minor release of docusate HIPs from all SEDDS (<2.7% within 4 h). In conclusion, highly lipophilic HIPs remain inside the oily phase of SEDDS and likely reach the absorption membrane in intact form.

Preparation and Evaluation of Charge Reversal Solid Lipid Nanoparticles.

The aim of this study was to design and investigate solid lipid nanoparticles (SLN) providing an intestinal alkaline phosphatase (IAP) triggered charge reversion. SLN containing the monophosphate ester bearing surfactant P-PEG-9-lauryl ether and the cationic surfactant benzalkonium chloride were prepared via step-wise hot microemulsion method enabling P-PEG-9-lauryl ether to accumulate the phosphate moiety on the surface of the particles accessible for IAP. Charge reversal SLN were characterized in vitro and ex vivo. SLN containing 10% of P-PEG-9-lauryl ether and 1% of cationic surfactant displayed a z-average of 92 nm and a PDI of 0.33 remaining stable over one year stored at 2-8 °C. An enzyme induced charge reversion from -18.4 mV to +16.5 mV correlated with the cleavage of 82% of the incorporated phosphate. SLN maintained their size during charge reversion, as no significant difference in z-average was observed. Mucin interaction studies revealed a higher interaction between SLN and mucins in the presence of IAP causing an increase in z-average from 190 nm to 2500 nm as well as a decrease in zeta potential from -26 mV to -17 mV. No significant change in z-average and zeta potential was observed when IAP was absent indicating lower mucin interaction of negatively charged particles. In contrast, higher interaction with cell membrane was evidenced by 85% hemolysis when SLN were pretreated with IAP, whereas control SLN without IAP resulted in 16% hemolysis. To investigate the phosphate cleavage by membrane bound IAP, SLN were incubated on excised rat intestinal mucosa and a significant higher release of phosphate was observed in comparison to samples treated with an enzyme inhibitor. Charge reversal SLN might be promising drug delivery systems for alkaline phosphatase bearing membranes that are covered by a mucus gel layer such as the intestine.

Charge-reversal nanoemulsions: A systematic investigation of phosphorylated PEG-based surfactants.

Surfactants bearing monophosphate esters with PEG of increasing chain length and different lipophilic tail structures were investigated to improve the effectiveness of enzyme triggered charge-converting nanoemulsions. The surfactants PEG-8-stearate, PEG-22-tocopheryl succinate (TPGS), PEG-3-oleate, PEG-9-oleate and PEG-9-lauryl ether were phosphorylated and incorporated in a self-emulsifying drug delivery system (SEDDS) exhibiting a defined PEG corona. To provide a positive zeta potential increasing amounts of the cationic surfactant benzalkonium chloride (BA) were incorporated. The effect of these PEG monophosphate esters (P-PEG-surfactants) was evaluated based on enzyme induced phosphate release and change in zeta potential. Significant enzyme induced charge conversion was observed for all P-PEG-surfactants, showing shifts from Δ3 mV to Δ31 mV. Surfactants comprising the shortest and longest PEG chain showed similar amplitudes (P-PEG-3-oleate: Δ11.9 mV; P-PEG-22-TPGS Δ10.2 mV), whereas P-PEG-8-stearate, P-PEG-9-oleate and P-PEG-9-lauryl ether bearing similarly long PEG chains but different lipophilic tail structures resulted in pronounced differences in amplitudes of Δ10.3 mV, Δ14.5 mV and Δ18.1 mV, respectively. Furthermore, an indirect correlation between the lipophilicity of P-PEG-surfactants and the obtained charge-reversing effect was observed. With the exception of P-PEG-lauryl ether, this charge-reversal effect decreased with increasing BA concentrations. In conclusion, the enzyme induced amplitude of charge conversion of P-PEG-surfactants depends to a high extent on their lipophilic tail structure. Based on this knowledge potent charge-reversal nanoemulsions can be designed.

Thiolated Chitosans: A Multi-talented Class of Polymers for Various Applications.

Various properties of chitosan can be customized by thiolation for very specific needs in a wide range of application areas. Since the discovery of thiolated chitosans, many studies have proven their advantageous characteristics, such as adhesion to biological surfaces, adjustable cross-linking and swelling behavior, controllable drug release, permeation as well as cellular uptake enhancement, inhibition of efflux pumps and enzymes, complexation of metal ions, antioxidative properties, and radical scavenging activity. Simultaneously, these polymers remain biodegradable without increased toxicity. Within this Review, an overview about the different possibilities to covalently attach sulfhydryl ligands to the polymeric backbone of chitosan is given, and the resulting versatile physiochemical properties are discussed in detail. Furthermore, the broad spectrum of applications for thiolated chitosans in science and industry, ranging from their most advanced use in pharmaceutical and medical science over wastewater treatment to the impregnation of textiles, is addressed.

Highly mucus permeating and zeta potential changing self-emulsifying drug delivery systems: A potent gene delivery model for causal treatment of cystic fibrosis.

AIM: It was the aim of the study to develop self-emulsifying drug delivery systems (SEDDS) with the ability to change their zeta potential towards higher values at the adsorption membrane and in this way facilitate the release of the DNA-cetrimonium complex and enhance transfection. METHODS: Plasmid DNA was complexed via hydrophobic ion pairing utilizing various surfactants and the complex was incorporated into SEDDS achieving a payload of 1% (m/v). Log PSEDDS/water of the complex was determined. SEDDS were characterized regarding droplet size, zeta potential, stability and toxicity. Alkaline phosphatase presented in the sputum of cystic fibrosis patients was quantified using 4-nitrophenyl phosphate disodium salt and 5-bromo-4-chloro-1H-indol-3-yl phosphate dipotassium salt as substrates. SEDDS containing 0.4% (m/v) 1,2-dipalmitoyl-sn-glycero-3-phosphate monosodium salt were characterized regarding their zeta potential changing properties utilizing isolated alkaline phosphatase and cystic fibrosis sputum. The mucus permeating properties of SEDDS were evaluated via Transwell method using cystic fibrosis sputum. Finally, the transfection efficiency of incorporated plasmid DNA was investigated. RESULTS: Cetrimonium bromide showed the highest precipitation efficiency of 99.5 ±â€¯2.72% for the complexation of pDNA. SEDDS containing propylene glycol, Capmul PG-8, Captex 300, Captex 355, Captex 8000, Cremophor EL, Cremophor RH-40 and Brij O10 showed stable emulsions with a droplet size between 20 and 100 nm and zeta potential <-3 mV over 4 h. SEDDS demonstrated highly protective effect against enzymatic degradation and moderate cell viability on freshly obtained pulmonary tissue. The pDNA-cetrimonium complex incorporated into SEDDS revealed a log PSEDDS/water of about 2. A concentration of 0.879 ±â€¯0.103 U/g alkaline phosphatase was found in the sputum of cystic fibrosis patients. SEDDS containing 1,2-dipalmitoyl-sn-glycero-3-phosphate monosodium salt showed a high potential of changing the zeta potential by applying isolated alkaline phosphatase as well as cystic fibrosis sputum along with high mucus permeating properties. Formulation C demonstrated the highest transfection efficiency with a 7.2-fold increased fluorescence intensity compared to naked pDNA. CONCLUSION: The novel developed zeta potential changing SEDDS are opening versatile opportunities for the treatment of cystic fibrosis caused by gene mutation.