Salmon calcitonin (sCT) is a peptide with poor enzymatic stability and permeability, limiting its oral delivery. This study investigated how hydrophobic ion pair (HIP) type and self-nanoemulsifying drug delivery systems (SNEDDS) composition influence the oral delivery of sCT, and whether in vitro findings correlate with in vivo outcomes. HIPs were prepared with sodium caprate (C10) or sodium docusate (DOC) and incorporated into two SNEDDS differing in a single excipient: F1 contained 10% lysophosphatidylcholine (LPC), a natural permeation enhancer, while F2 replaced LPC with propylene glycol. In vitro, sCT:C10 provided no protection against trypsin, whereas sCT:DOC did (p < 0.05 vs native sCT). Incorporating HIPs into SNEDDS enhanced sCT proteolytic stability against trypsin relative to native sCT, but the extent was formulation-dependent, with F1 showing lower protection than F2 for the same HIP. Permeability in Caco-2 cells was mainly driven by SNEDDS, with F1 consistently showing lower FD4 transport than F2, indicating no additional benefit from LPC. In vivo, sCT:C10 showed no significant difference in relative pharmacological activity (PArel) over native sCT, whereas sCT:DOC significantly increased activity. HIP-loaded SNEDDS enhanced sCT activity compared with native sCT, yet F1 did not improve activity beyond F2. Among all groups, sCT:DOC in F2 achieved the highest PArel (8.8 ± 0.8%), indicating more favourable conditions for sCT oral delivery. In addition, in vitro trends correlated well with in vivo outcomes. Overall, HIP type and SNEDDS composition significantly influenced oral sCT delivery, highlighting the need to co-optimize these parameters to achieve effective oral peptide delivery.

Semaglutide (SET) is a glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes. Although injectable formulations offer high bioavailability, they are associated with poor patient compliance. In contrast, oral tablets are more convenient but suffer from limited absorption due to SET's hydrophilicity and enzymatic instability in the gastrointestinal tract. To address these challenges, we developed a hydrophobic ion pair (HIP) complex of SET and sodium docusate (SET-DOC), which was further incorporated into a self-emulsifying drug delivery system (SD@SEDDS) to facilitate oral delivery. The optimized SD@SEDDS produced a clear emulsion upon dilution, with a uniform particle size of 85.55 nm, high drug loading (2.64 mg/g), and excellent stability. In vitro transport studies using a Caco-2/HT-29 co-culture model demonstrated enhanced permeability and reduced P-glycoprotein-mediated efflux. In vivo studies in a type 2 diabetic rat model showed that SD@SEDDS significantly reduced blood glucose levels, improved lipid profiles, and exhibited good biocompatibility without observable toxicity. These findings suggested that the combination of HIP technology and SEDDS represented a promising strategy for enhancing the oral delivery efficiency of peptide drugs such as SET.

Enzyme-catalyzed reactions rely on the precise regulation of enzymatic activity to achieve high efficiency and specificity. Adjustment of conditions during the reaction is only one possibility, whereas timely activation and termination of enzymatic functions further tailor the outcomes. Existing methods for enzyme activation include temperature, pH, ultrasound, and magnetic and electric fields, but each approach struggles with limited applicability to different enzyme classes and faces challenges with reversibility. In our research, we employed hydrophobic ion pairing to modulate lysozyme activity through complexation with hydrophobic counterions, sodium docusate, and sodium laurate. The resulting complex agglomerates were stabilized with nonionic surfactants and characterized by their colloidal properties, including size and zeta potential. A fluorescence-based enzymatic assay was used to monitor the activity of the nanosystems under varying dissociation conditions. Lysozyme nanosystems with sodium docusate were completely inactivated, while those with sodium laurate retained only a partial activity. Increasing the ionic strength reversed the inactivation and restored enzymatic function. We developed a method for reversible, conditional modulation of enzymatic activity as a function of the ionic concentration. This work demonstrates a tunable strategy for regulating enzyme activity in cases where conventional control mechanisms are not suitable.

Oral delivery of peptides is a promising alternative to invasive injectable therapies, offering improved patient adherence and convenience. Glucagon-like peptide-1 (GLP-1) analogs, in particular, are highly effective for the management of type 2 diabetes mellitus and obesity, yet their oral bioavailability remains limited by enzymatic degradation and poor intestinal permeability.

Amyloid fibrillation caused by ligand binding is a double-edged process that plays a critical role in shedding light on neurodegenerative disorders. In this work, we explored how the anionic surfactant dioctyl sulfosuccinate sodium salt (DOSS) induces amyloid fibril formation of hen egg-white lysozyme (HEWL) in a concentration-dependent manner at pH 7.5. Our biophysical studies showed that upon addition of 800 μM DOSS, HEWL undergoes structural rearrangements from α-helical to β-sheet conformations, with the highest aggregation occurring at moderate (300-1000 μM) DOSS levels. In contrast, at very high surfactant concentrations (>1000 μM), it leads to another structural modification. Molecular dynamics simulations suggested that DOSS causes subtle expansion and increased flexibility in HEWL, promoting aggregation without causing major unfolding. We further examined the roles of different cosolutes on DOSS-induced aggregates: Polyethylene Glycol 4000 (PEG 4000) helps stabilize them; sucrose suppresses aggregation by favoring the native state; and ethanol has a dual effect: it enhances aggregation at low concentrations (up to 20%) and solubilizes aggregates at higher concentrations. These results illuminate the intricate balance between surfactants and the solvent environment in directing amyloid formation. Looking ahead, these mechanistic insights could guide the development of therapies that selectively prevent harmful aggregation. Additionally, understanding these interactions is essential for designing biopharmaceutical formulations to avoid unintended protein aggregation in therapeutic products.

Introduction: Achieving sustained local antibiotic concentrations is critical for managing orthopedic infections. This proof-of-concept study evaluated release kinetics, local/systemic concentrations, and histological responses to CarboCell G/C, an injectable gentamicin- and clindamycin-eluting depot in a porcine bone void model. Methods: CarboCell G/C containing 111 mg g-1 gentamicin-docusate and 70 mg g-1 clindamycin was injected into and around a tibial bone void in 11 pigs. Antibiotic concentrations in target tissues and systemic spillover were measured at 1-12 h by microdialysis and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and in tissue homogenates at 1, 3, and 7 d. Release was quantified by high-performance liquid chromatography (HPLC), and tolerability was assessed histologically. Results: Microdialysis showed high stable antibiotic tissue levels during the first 12 h with minimal systemic spillover. Peak gentamicin and clindamycin concentrations in bone were 730 ± 170 and 3700 ± 700 µ g g-1 and 42 ± 15 and 360 ± 120 µ g g-1 in soft tissue, respectively. Tissue half-lives ranged from 43-62 h for clindamycin and 40-46 h for gentamicin. Recovered depots had released ∼ 30 %-50 % of their antibiotic content at day 1 and ∼ 60 %-80 % by day 7. Depots elicited a mild-moderate local inflammatory response. Conclusion: CarboCell G/C provides sustained high local antibiotics for at least 7 d with minimal systemic spillover, supporting further evaluation in orthopedic infection management.

Impaired GI tract function is a common and often underappreciated symptom in the Medical Intensive Care Unit (MICU). The most visible manifestation of this dysfunction is reduced bowel movements. The occurrence of impaired GI function is associated, both independently and in association with delayed enteral feeding, with increased length of stay, morbidity and mortality. We report on a process implementation project conducted at a single academic center designed to: (I) increase visibility of bowel movement charting and (II) transition from a reactive to a proactive laxative administration regimen for prophylaxis against MICU associated constipation. Scheduled laxatives, polyethylene glycol and sennoside-docusate, were added to the MICU admission orderset and bowel movement charting was moved to a more readily accessible flowsheet in the electronic medical record. Six months of pre-intervention and post-intervention admissions to the MICU were reviewed to determine patient demographics, admitting diagnosis, Sequential Organ Failure Assessment (SOFA) score, laxative utilization, and time to first bowel movement. Following implementation of these changes, prophylactic laxative utilization significantly increased (p < .001) driven largely by the agents included in the orderset. This was associated with a decrease in MICU length of stay by an average of 21 h (p = .006) and median time to first bowel movement by 4 h (p = .026), but no changes in incidence of impaired transit (as defined by greater than 72 h without a bowel movement). This data represents an exciting first step in the use of mixed agent prophylactic laxative regimens.

We have demonstrated the efficacy of a novel strategy for achieving the prolonged and sustained release of vancomycin as a prophylaxis against surgical site infection (SSI). This strategy uses hydrophobic ion pairing (HIP), joining vancomycin with counter ions and efficiently encapsulating the antibiotic in biodegradable polymer nanospheres. To complete the process, vancomycin-complexes were formed in an aqueous acidic medium, and then they were encapsulated in poly(lactic-co-glycolic) acid (PLGA), polylactic acid (PLA), and polycaprolactone (PCL) nanospheres via the double-emulsion solvent-evaporation method. Our results show that sulfate and sulfonate-based counter ions provide the most effective structure for vancomycin-HIP formation, achieving 95% complexation efficiency at a 1:2 molar ratio. Once formed, the vancomycin-dioctyl sodium sulfosuccinate (Van-DOSS) complex achieved a 3.7-fold increase in lipophilicity (LogP octanol/water), which significantly improved encapsulation efficiency in comparison to unmodified vancomycin. Encapsulation efficiency increased by 2.7-fold in PLGA (64.7% ± 0.4%) and by 5.5-fold in PLA (46.7 ± 5.9%) and PCL (47.7 ± 6.9%). The Van-HIP nanospheres achieved an in-vitro release of vancomycin that was three-to-five times the minimum inhibitory concentration required for S. aureus over the critical 28-day window indicated for post-operative care after spine surgery. Consequently, these findings support a sustained-release option for antibiotic formulation to improve surgical outcomes.

Background Constipation affects many critically ill patients and may lead to discomfort, prolonged hospital stay, or mortality. Standardised bowel protocols are recommended to improve patient care. This audit evaluates the adherence to the bowel protocol at the Intensive Care Unit (ICU) at Royal Liverpool University Hospital, before and after educational interventions. Methods Adult ICU patients aged 18 and above were included. Patients who had post-gastroenterological surgery, hepatic encephalopathy, bowel obstruction/ischaemia, or spinal cord injury were excluded from this study. Data were collected from paper charts and the internal hospital electronic system. Two four-week cycles of data were collected (20/05/2024-16/06/2024, 10/07/2024-07/08/2024), with the intervention of the delivery of educational sessions and posters implemented between the two cycles. Results In the first cycle, 50 patients were assessed: 14 medical and 36 surgical. Enteral feeding within 48 hours occurred in 100% of medical and 88.9% of surgical patients. Senna and docusate were prescribed in 50% of medical and 25% of surgical patients on admission. Bowel movements within 48 hours occurred in 64.3% of medical and 36.1% of surgical patients (p=0.113 when comparing within the first cycle). In the second cycle, 48 patients were included: 10 medical and 38 surgical. Senna and docusate were prescribed in 90% of medical patients, with 90% achieving bowel movements within 48 hours. Surgical patients showed lower adherence, with 13.2% prescribed senna and docusate and 21.1% opening bowels within 48 hours. Within the second cycle, the difference in the onset of bowel motion between medical and surgical patients was statistically significant (p=0.0001). However, no statistical changes were found comparing the first and second cycles in medical and surgical patients prospectively.  Conclusion The outcome of this audit suggests, but does not confirm, that educational interventions may positively impact the adherence to bowel protocol in ICU patients. Surgical patients demonstrated limited change due to post-operative care plans determined by parent teams. Ongoing education is essential for optimising the compliance of bowel protocol in the ICU.

The design of inverse micelles represents a specific biomedical interest for drug delivery. We hereby investigate interactions between the docusate sodium (AOT) surfactant, n-heptane non-polar phase, diethyl sulfoxide (DESO), water, and a p-nitroaniline (NA) molecular probe. NA is hereby also used as an approximation of a drug molecule. The low-energy stationary points, representing the chosen chemical compositions, were determined via the global minimum search and confirmed at the hybrid DFT level of theory. At a small polar phase content to surfactant content ratio (Ws = 0…2), the Na-ion strongly coordinates the polar head of AOT, involving four oxygen atoms. In turn, the head group of AOT exhibits negligible binding with DESO. In all stationary configurations, DESO and water compete with the headgroup of AOT to coordinate the Na-ion. In the absence of a polar phase, NA maintains an H-bond with AOT. The increase in the polar phase fraction (Ws = 2…10) suppresses NA to AOT binding, while boosting sodium solvation by DESO and water. Numerous competitive interactions at various Ws parameters were discussed. Infrared and UV/Vis spectra were computed to bridge simulations with experiments. The reported theoretical data rationalize and supplement existing experimental insights into polar phases confined by AOT inverse micelles.

Zika Virus (ZIKV) is a mosquito-borne virus that can cause serious health problems, including birth defects and neurological complications. Unfortunately, there are no antivirals currently approved for its treatments. In this study, we tested a library of 348 chemical compounds to find potential candidates that could block ZIKV infection. Seven compounds showed strong antiviral activity in laboratory experiments. Among them, Cephalotaxine, Docusate Sodium, and Saikosaponin B2 were the most effective. However, Docusate Sodium may pose safety risks at higher doses, and Saikosaponin B2 has poor solubility, which could limit its use as a drug. To better understand how these compounds work, molecular docking was employed to predict interactions between the active compounds and two important ZIKV proteins: NS5 and the NS2B-NS3 protease complex. The docking results supported the in vitro findings, revealing strong binding affinities, particularly for Saikosaponin B2. Molecular dynamics simulations confirmed stable binding of Saikosaponin B2 and Aloperine to NS5, with Saikosaponin B2 showing greater stability and consistent interactions. Drug-likeness and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis indicated that while some compounds possess favorable pharmacokinetic properties, others may require structural optimization. Overall, this study identifies several promising lead compounds for further preclinical development and highlights the utility of integrating in vitro screening with computational modeling to accelerate antiviral drug discovery against ZIKV.