In vitro evaluation of natural and methylated cyclodextrins as buccal permeation enhancing system for omeprazole delivery

http://www.sciencedirect.com/science/article/B6T6C-4TB1846-1/2/58c971bfdf400a5dd4f0dfc5d9c2350

Thiolated silicone oil: Synthesis, gelling and mucoadhesive properties

AbstractThe aim of this study was the development of novel thiolated silicone oils and their evaluation with regard to gelling and mucoadhesive properties. A thiol coupling of 220±14 and 127±33μmol/g polymer for 3-mercaptopropionic acid (MPA)- and cysteine-coupled silicone oil was determined, respectively. The dynamic viscosity of MPA–silicone raised significantly (p<0.000001) after oxidation with iodine to a maximum of 523-fold within 1h. During tensile studies, MPA–silicone showed both the highest results for total work of adhesion (TWA) and maximum detachment force (MDF) with a 3.8- and 3.4-fold increase, respectively, compared to the control. As far as the residence time on small intestinal mucosa is concerned, both silicone conjugates were detectable in almost the same quantities for up to 8h with 56.9±3.3 and 47.8±8.9% of the initially applied conjugated silicone oil. Thiolated silicone oils can be regarded superior in comparison to commonly used silicone oils due to a prolonged retention time in the small intestine as site of action. Gelling and mucoadhesive features are advantageous for antiflatulent as well as mucoprotective biomaterials. Thus, these novel thiomers seem promising for an upgrade of currently available products for the treatment of dyspepsia, reflux oesophagitis and even inflammatory bowel diseases such as ulcerative colitis or Crohn’s disease

Chemical coupling of thiolated chitosan to preformed liposomes improves mucoadhesive properties

Kerstin Gradauer,1 Caroline Vonach,1 Gerd Leitinger,2,3 Dagmar Kolb,2,3 Eleonore Fr&amp;ouml;hlich,3 Eva Roblegg,4 Andreas Bernkop-Schn&amp;uuml;rch,5 Ruth Prassl1,61Institute of Biophysics and Nanosystems Research, Austrian Academy of Sciences, Graz, Austria; 2Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria; 3Center for Medical Research, Medical University of Graz, Graz, Austria; 4Institute of Pharmaceutical Sciences/Pharmaceutical Technology, Karl-Franzens University, Graz, Austria; 5Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria; 6Ludwig Boltzmann Institute for Lung Vascular Research, Graz, AustriaAim: To develop mucoadhesive liposomes by anchoring the polymer chitosan-thioglycolic acid (chitosan-TGA) to the liposomal surface to target intestinal mucosal membranes.Methods: Liposomes consisting of phosphatidylcholine (POPC) and a maleimide-functionalized lipid were incubated with chitosan-TGA, leading to the formation of a thioether bond between free SH-groups of the polymer and maleimide groups of the liposome. Uncoated and newly generated thiomer-coated liposomes were characterized according to their size, zeta potential, and morphology using photon correlation spectroscopy and transmission electron microscopy. The release behavior of calcitonin and the fluorophore/quencher-couple ANTS/DPX (8-aminonaphthalene-1,3,6-trisulfonic acid/p-xylene-bis- pyridinium bromide) from coated and uncoated liposomes, was investigated over 24 hours in simulated gastric and intestinal fluids. To test the mucoadhesive properties of thiomer-coated and uncoated liposomes in-vitro, we used freshly excised porcine small intestine.Results: Liposomes showed a concentration-dependent increase in size &amp;ndash; from approximately 167 nm for uncoated liposomes to 439 nm for the highest thiomer concentration used in this study. Likewise, their zeta potentials gradually increased from about &amp;ndash;38 mV to +20 mV, clearly indicating an effective coupling of chitosan-TGA to the surface of liposomes. As a result of mucoadhesion tests, we found an almost two-fold increase in the mucoadhesion of coupled liposomes relative to uncoupled ones. With fluorescence microscopy, we saw a tight adherence of coated particles to the intestinal mucus.Conclusion: Taken together, our current results indicate that thiomer-coated liposomes possess a high potential to be used as an oral drug-delivery system.Keywords: thiomer, liposome, mucoadhesion, chitosan-thioglycolic acid, oral drug deliver

Bioadhesive properties of poly(anhydride) nanoparticles coated with different molecular weights chitosan

The aim of this study was to develop and characterize the bioadhesive properties of poly(anhydride) nanoparticles coated with two types of low-molecular weight chitosan (CH20 of 20?kDa or CH50 of 50?kDa) or their thiolated conjugates. Nanoparticles were prepared by a solvent displacement method and characterized by measuring the size, zeta potential, morphology and composition. For bioadhesion studies, nanoparticles were fluorescently labelled with rhodamine B isothiocyanate. In all cases, coated nanoparticles showed a slightly higher size and lower negative zeta potential than uncoated nanoparticles. Nanoparticles coated with CH20 showed a higher adhesive capacity than uncoated nanoparticles. On the contrary, when nanoparticles were coated with CH50, the resulting carriers displayed a decreased ability to develop adhesive interactions within the gut. Finally, the coating of nanoparticles with thiolated chitosan improved their adhesive abilities. Poly(anhydride) nanoparticles coated with thiolated chitosan can be considered as promising bioadhesive particulate carriers for oral delivery strategies.Fil: Llabot, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; ArgentinaFil: Hesham, Salman. Universidad de Navarra; EspañaFil: Millotti, Gioconda. Universidad de Innsbruck; AustriaFil: Bernkop Schnürch, Andreas. Universidad de Innsbruck; AustriaFil: Allemandi, Daniel Alberto. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Manuel Irache, Juan. Universidad de Navarra; Españ

Nanoparticle diffusion within intestinal mucus: Three-dimensional response analysis dissecting the impact of particle surface charge, size and heterogeneity across polyelectrolyte, pegylated and viral particles

Multiple particle tracking (MPT) methodology was used to dissect the impact of nanoparticle surface charge and size upon particle diffusion through freshly harvested porcine jejunum mucus. The mucus was characterised rheologically and by atomic force microscopy. To vary nanoparticle surface charge we used a series of self-assembly polyelectrolyte particles composed of varying ratios of the negatively charged polyacrylic acid polymer and the positively charged chitosan polymer. This series included a neutral or near-neutral particle to correspond to highly charged but near-neutral viral particles that appear to effectively permeate mucus. In order to negate the confounding issue of self-aggregation of such neutral synthetic particles a sonication step effectively reduced particle size (to less than 340 nm) for a sufficient period to conduct the tracking experiments. Across the polyelectrolyte particles a broad and meaningful relationship was observed between particle diffusion in mucus (×1000 difference between slowest and fastest particle types), particle size (104–373 nm) and particle surface charge (−29 mV to +19.5 mV), where the beneficial characteristic promoting diffusion was a neutral or near-neutral charge. The diffusion of the neutral polyelectrolyte particle (0.02887 cm S−1 × 10−9) compared favourably with that of a highly diffusive PEGylated-PLGA particle (0.03182 cm2 S−1 × 10−9), despite the size of the latter (54 nm diameter) accommodating a reduced steric hindrance with the mucin network. Heterogeneity of particle diffusion within a given particle type revealed the most diffusive 10% sub-population for the neutral polyelectrolyte formulation (5.809 cm2 S−1 × 10−9) to be faster than that of the most diffusive 10% sub-populations obtained either for the PEGylated-PLGA particle (4.061 cm2 S−1 × 10−9) or for a capsid adenovirus particle (1.922 cm2 S−1 × 10−9). While this study has used a simple self-assembly polyelectrolyte system it has substantiated the pursuance of other polymer synthesis approaches (such as living free-radical polymerisation) to deliver stable, size-controlled nanoparticles possessing a uniform high density charge distribution and yielding a net neutral surface potential. Such particles will provide an additional strategy to that of PEGylated systems where the interactions of mucosally delivered nanoparticles with the mucus barrier are to be minimised

Targeted Self-Emulsifying Drug Delivery Systems to Restore Docetaxel Sensitivity in Resistant Tumors

The use of chemotherapeutic agents such as docetaxel (DTX) in anticancer therapy is often correlated to side effects and the occurrence of drug resistance, which substantially impair the efficacy of the drug. Here, we demonstrate that self-emulsifying drug delivery systems (SEDDS) coated with enoxaparin (Enox) are a promising strategy to deliver DTX in resistant tumors. DTX partition studies between the SEDDS pre-concentrate and the release medium (water) suggest that the drug is well retained within the SEDDS upon dilution in the release medium. All SEDDS formulations show droplets with a mean diameter between 110 and 145 nm following dilution in saline and negligible hemolytic activity; the droplet size remains unchanged upon sterilization. Enox-coated SEDDS containing DTX exhibit an enhanced inhibition of cell growth compared to the control on cells of different solid tumors characterized by high levels of FGFR, which is due to an increased DTX internalization mediated by Enox. Moreover, only Enox-coated SEDDS are able to restore the sensitivity to DTX in resistant cells expressing MRP1 and BCRP by inhibiting the activity of these two main efflux transporters for DTX. The efficacy and safety of these formulations is also confirmed in vivo in resistant non-small cell lung cancer xenografts

Impact of different hydrophobic ion pairs of octreotide on its oral bioavailability in pigs

The objective of this study was to investigate the impact of different hydrophobic ion pairs (HIP) on the oral bioavailability of the model drug octreotide in pigs. Octreotide was ion paired with the anionic surfactants deoxycholate, decanoate and docusate differing in lipophilicity. These hydrophobic ion pairs were incorporated in self-emulsifying drug delivery systems (SEDDS) based on BrijO10, octyldodecanol, propylene glycol and ethanol in a concentration of 5 mg/ml. SEDDS were characterized regarding size distribution, zeta potential, stability towards lipase, log DSEDDS/release medium and mucus diffusion behavior. The oral bioavailability of octreotide was evaluated in pigs via LC-MS/MS analyses. Most efficient ion pairing was achieved at a molar ratio of 1:3 (peptide: surfactant). SEDDS containing the octreotide-deoxycholate, -decanoate and -docusate ion pair exhibited a mean droplet size of 152 nm, 112 nm and 191 nm and a zeta potential of − 3.7, − 4.6 and − 5.7 mV, respectively. They were completely stable towards degradation by lipase and showed a log DSEDDS/release medium of 1.7, 1.8 and 2.7, respectively. The diffusion coefficient of these SEDDS was in the range of 0.03, 0.11 and 0.17 × 10− 9 cm2/s, respectively. In vivo studies with these HIPs showed no improvement in the oral bioavailability in case of octreotide-decanoate. In contrast, octreotide-deoxycholate and octreotide-docusate SEDDS resulted in a 17.9-fold and 4.2-fold higher bioavailability vs. control. According to these results, hydrophobic ion pairing could be identified as a key parameter for SEDDS to achieve high oral bioavailability

Current challenges and future perspectives in oral absorption research: An opinion of the UNGAP network

Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research.European Cooperation in Science and Technology CA16205National Centre for Research and Development POIR.01.02.00-00-0011/17Ministry of Education, Youth and Sports of the Czech Republic TC19039, LTC18003Czech Science Foundation 18-00132

In vivo evaluation of an oral self-emulsifying drug delivery system (SEDDS) for exenatide

Background The aim of the study was to develop an oral self-emulsifying drug delivery system (SEDDS) for exenatide and to evaluate its in vivo efficacy. Methods Exenatide was lipidised via hydrophobic ion pairing with sodium docusate (DOC) and incorporated in SEDDS consisting of 35% Cremophor EL, 25% Labrafil 1944, 30% Capmul-PG 8 and 10% propylene glycol. Exenatide/DOC was characterized in terms of lipophilicity evaluating the octanol/water phase distribution (logP). Exenatide/DOC SEDDS were characterized via droplet size analysis, drug release characteristics (log DSEDDS/release medium determination) and mucus permeation studies. Furthermore, the impact of orally administered exenatide/DOC SEDDS on blood glucose level was investigated in vivo on healthy male Sprague-Dawley rats. Results Hydrophobic ion pairing in a molar ratio of 1:4 (exenatide:DOC) increased the effective logP of exenatide from −1.1 to 2.1. SEDDS with a payload of 1% exenatide/DOC had a mean droplet size of 45.87 ± 2.9 nm and a Log DSEDDS/release medium of 1.9 ± 0.05. Permeation experiments revealed 2.7-fold improved mucus diffusion for exenatide/DOC SEDDS compared to exenatide in solution. Orally administered exenatide/DOC SEDDS showed a relative bioavailability (versus s.c.) of 14.62% ± 3.07% and caused a significant (p < .05) 20.6% decrease in AUC values of blood glucose levels. Conclusion According to these results, hydrophobic ion pairing in combination with SEDDS represents a promising tool for oral peptide delivery

Mucus permeating thiolated self-emulsifying drug delivery systems

Context Mucus represents a critical obstacle for self-emulsifying drug delivery systems (SEDDS) targeting the epithelial membrane site. Objective The aim of the study was the development of a novel SEDDS to overcome the mucus barrier. Materials and methods Two novel conjugates N-dodecyl-4-mercaptobutanimidamide (thiobutylamidine-dodecylamine, TBA-D) and 2-mercapto-N-octylacetamide (thioglycolic-acid-octylamine, TGA-O) were synthesized, incorporated into SEDDS and analyzed for stability, cytotoxicity and physico-chemical characteristics using dynamic light scattering. Mucus interaction studies were performed using in-vitro assays based on multiple particle tracking, rotational silicone tubes and rheology. Results and discussion TBA-D was synthesized using dodecylamine and iminothiolane as thiol precursor (yield = 55 ± 5%). TGA-O was obtained via crosslinking of octylamine with SATA ((2,5-dioxopyrrolidin-1-yl) 2-acetylsulfanylacetate) (yield = 70 ± 6%). The chemical structure of target compounds was confirmed via NMR analysis. The thiol-conjugates were incorporated in an amount of 3% (m/m) into SEDDS (Cremophor EL 30%, Capmul MCM 30%, Captex 355 30% and propylene glycol 10%), namely thiolated SEDDS leading to a droplet size around 50 nm and zeta potential close to 0 mV. Thiolated SEDDS with an effective diffusion coefficient 〈Deff〉 of up to 0.871 ± 0.122 cm2 s−1 × 10−9 were obtained. Rotational silicone studies show increased permeation of the thiolated SEDDS A in comparison with unthiolated control. Rheological studies confirmed the mucolytic activity of the thiol-conjugates which differed only by 3% from DTT (dithiothreitol) serving as positive control. Conclusion Low molecular weight thiol-conjugates were identified to improve the mucus permeation, leading to highly efficient mucus permeating SEDDS, which were superior to conventional SEDDS and might thus be a new carrier for lipophilic drug delivery