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Acta Biomaterialia Dec 2021Hydrophobic drugs are incorporated into oil-in-water nanoemulsions (OIW) either as new formulations or repurposed for intravenous delivery. Typically, these are...
Hydrophobic drugs are incorporated into oil-in-water nanoemulsions (OIW) either as new formulations or repurposed for intravenous delivery. Typically, these are manufactured through stepwise processes of sonication or high-pressure homogenization (HPH). The guiding criteria for most nanoemulsion manufacture are the size and homogeneity/polydispersity of the drug-laden particles with strict requirements for clinical injectables. To date, most formulation optimization is done through trial and error with stepwise sampling during processing utilizing dynamic light scattering (DLS), light obscuration sensing (LOS) or laser particle tracking (LPT) to assess manufacturing progress. The objective of this work was to develop and implement an in-line optical turbidity/nephelometry sensor array for the longitudinal in-process monitoring of nanoemulsion manufacture. A further objective was the use of this sensor array to rapidly optimize the manufacture of a sub-120 nm oxygen carrying perfluorocarbon nanoemulsion with a non-synthetic stabilizer. During processing, samples were taken for particle size measurement and further characterization. There was a significant correlation and agreement between particle size and sensor signal as well as improved process reproducibility through sensor-guided manufacture. Given the cost associated with nanoemulsion development and scale-up manufacture, our sensor arrays could be an invaluable tool for efficient and cost-effective drug development. Sensor-guided manufacturing was used to optimize oxygen-carrying nanoemulsions. These were tested, in vitro, for their ability to improve the viability of encapsulated endocrine clusters (mouse insulinoma, Min6) and to eliminate hypoxia due to oxygen mass transfer limitations. The nanomulsions significantly improved encapsulated cluster viability and reduced hypoxia within the microcapsule environment. STATEMENT OF SIGNIFICANCE: Nanoemulsions are rapidly becoming vehicles for the controlled release delivery of both hydrophilic and hydrophobic drugs given their large surface area for exchange. As work shifts from bench to large scale manufacturing, there is a critical need for technologies that can monitor and accumulate data during processing, particularly regarding the endpoint criteria of particle size and stability. To date, no such technology has been implemented in nanoemulsion manufacture. In this paper we develop and implement an optical sensor array for in-line nanoemulsion process monitoring and then use the array to optimize the development and manufacture of novel reproducible oxygen carrying nanoemulsions lacking synthetic surfactants.
Topics: Animals; Emulsions; Fluorocarbons; Mice; Particle Size; Reproducibility of Results; Surface-Active Agents
PubMed: 34563723
DOI: 10.1016/j.actbio.2021.09.038 -
Molecular Pharmaceutics Oct 2021Nanoemulsions are considered as the most promising solution to improve the delivery of ophthalmic drugs. The design of ophthalmic nanoemulsions requires an extensive... (Review)
Review
Nanoemulsions are considered as the most promising solution to improve the delivery of ophthalmic drugs. The design of ophthalmic nanoemulsions requires an extensive understanding of pharmaceutical as well as technological aspects related to the selection of excipients and formulation processes. This Review aims at providing the readers with a comprehensive summary of possible compositions of nanoemulsions, methods for their formulation (both laboratory and industrial), and differences between technological approaches, along with an extensive outline of the research methods enabling the confirmation of properties, pharmaceutical performance, and biological activity of the obtained product. The composition of the formulation has a major influence on the properties of the final product obtained with low-energy emulsification methods. Increasing interest in high-energy emulsification methods is a consequence of their scalability important from the industrial perspective. Considering the high-energy emulsification methods, both the composition and conditions of the process (e.g., device power level, pressure, temperature, homogenization time, or number of cycles) are important for the properties and stability of nanoemulsions. It is advisible to determine the effect of each parameter on the quality of the product to establish the optimal process parameters' range which, in turn, results in a more reproducible and efficient production.
Topics: Administration, Ophthalmic; Emulsions; Eye Diseases; Humans; Nanoparticle Drug Delivery System; Quality Control
PubMed: 34533317
DOI: 10.1021/acs.molpharmaceut.1c00650 -
Drug Delivery Dec 2021Nanogels have high tunability and stability while being able to sense and respond to external stimuli by showing changes in the gel volume, water content, colloidal... (Review)
Review
Nanogels have high tunability and stability while being able to sense and respond to external stimuli by showing changes in the gel volume, water content, colloidal stability, mechanical strength, and other physical/chemical properties. In this article, advances in the preparation of nanogels will be reviewed. The application potential of nanogels in drug delivery will also be highlighted. It is the objective of this article to present a snapshot of the recent knowledge of nanogel preparation and application for future research in drug delivery.
Topics: Chemistry, Pharmaceutical; Cross-Linking Reagents; Drug Carriers; Drug Liberation; Emulsions; Humans; Molecular Weight; Nanogels; Polymers
PubMed: 34308729
DOI: 10.1080/10717544.2021.1955042 -
Journal of Nanobiotechnology Dec 2021Combination therapy using more than one drug can result in a synergetic effect in clinical treatment of cancer. For this, it is important to develop an efficient drug...
BACKGROUND
Combination therapy using more than one drug can result in a synergetic effect in clinical treatment of cancer. For this, it is important to develop an efficient drug delivery system that can contain multiple drugs and provide high accumulation in tumor tissue. In particular, simultaneous and stable loading of drugs with different chemical properties into a single nanoparticle carrier is a difficult problem.
RESULTS
We developed rhamnolipid-coated double emulsion nanoparticles containing doxorubicin and erlotinib (RL-NP-DOX-ERL) for efficient drug delivery to tumor tissue and combination chemotherapy. The double emulsion method enabled simultaneous loading of hydrophilic DOX and hydrophobic ERL in the NPs, and biosurfactant RL provided stable surface coating. The resulting NPs showed fast cellular uptake and synergetic tumor cell killing in SCC7 cells. In real-time imaging, they showed high accumulation in SCC7 tumor tissue in mice after intravenous injection. Furthermore, enhanced tumor suppression was observed by RL-NP-DOX-ERL in the same mouse model compared to control groups using free drugs and NPs containing a single drug.
CONCLUSIONS
The developed RL-NP-DOX-ERL provided efficient delivery of DOX and ERL to tumor tissue and successful tumor therapy with a synergetic effect. Importantly, this study demonstrated the promising potential of double-emulsion NPs and RL coating for combination therapy.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Doxorubicin; Drug Therapy, Combination; Emulsions; Erlotinib Hydrochloride; Glycolipids; Mice; Nanoparticles; Optical Imaging
PubMed: 34876140
DOI: 10.1186/s12951-021-01160-4 -
BMC Cancer Dec 2022This research aimed to evaluate the feasibility of a novel liquid embolic agent Pickering gel emulsion of lipiodol (PGEL) for renal and hepatic artery embolization in...
OBJECTIVE
This research aimed to evaluate the feasibility of a novel liquid embolic agent Pickering gel emulsion of lipiodol (PGEL) for renal and hepatic artery embolization in the rabbit experimental model.
METHODS
Embolization was performed in the right renal artery of 24 adult New Zealand White rabbits and 24 VX2 tumors in the left liver lobe. The rabbits were randomly allocated to four treatment groups (n = 6 per group): (A) normal saline (NS), (B) lipiodol, (C) 180-300 μm polyvinyl alcohol (PVA), and (D) PGEL.
RESULTS
Renal artery embolization in normal rabbits and transarterial embolization (TAE) in VX2 tumor-bearing rabbits indicated that PGEL achieved a better embolization effect for a longer time than lipiodol and PVA. The tumor growth ratio of the PGEL group was significantly lower than that of the NS, lipiodol, and PVA groups at 3 (P < 0.001) and 7 (P < 0.001) days after embolization. In addition, hematoxylin and eosin and immunohistochemical staining revealed that the tumor necrosis ratio was higher in the PGEL group than in the NS, lipiodol, and PVA groups (P < 0.01), and the expression levels of HIF-1α, VEGF, and CD31 decreased after PGEL embolization compared with the lipiodol and PVA treatments.
CONCLUSION
PGEL is an effective embolic material that provides immediate and total occlusion of the renal artery and may be a potential therapeutic embolic agent for TAE of HCC.
Topics: Animals; Rabbits; Carcinoma, Hepatocellular; Embolization, Therapeutic; Emulsions; Ethiodized Oil; Hepatic Artery; Liver Neoplasms
PubMed: 36510170
DOI: 10.1186/s12885-022-10337-5 -
Molecules (Basel, Switzerland) Mar 2023Cefixime (CFX) belongs to a group of third-generation cephalosporin antibiotics with low water solubility and low intestinal permeability, which ultimately leads to...
BACKGROUND
Cefixime (CFX) belongs to a group of third-generation cephalosporin antibiotics with low water solubility and low intestinal permeability, which ultimately leads to significantly low bioavailability.
AIM
This study aimed to increase solubility, improve drug release, and intestinal permeability of CFX by loading into SEDDS.
METHODS
Suitable excipients were selected based on drug solubility, percent transmittance, and emulsification efficiency. Pseudo-ternary phase diagram was fabricated for the identification of effective self-emulsification region. The best probably optimized formulations were further assessed for encumbered drug contents, emulsification time, cloud point measurement, robustness to dilution, mean droplet size, zeta potential, polydispersity index (PDI), and thermodynamic and chemical stability. Moreover, in vitro drug release studies and ex vivo permeation studies were carried out and apparent drug permeability P of different formulations was compared with the marketed brands of CFX.
RESULTS
Amongst the four tested SEDDS formulations, F-2 formulation exhibited the highest drug loading of 96.32%, emulsification time of 40.37 ± 3 s, mean droplet size of 19.01 ± 1.12 nm, and demonstrated improved long-term thermodynamic and chemical stability when stored at 4 °C. Release studies revealed a drug release of 97.32 ± 4.82% within 60 min in simulated gastric fluid. Similarly, 97.12 ± 5.02% release of CFX was observed in simulated intestinal fluid within 120 min; however, 85.13 ± 3.23% release of CFX was observed from the marketed product. Ex vivo permeation studies displayed a 2.7-fold increase apparent permeability compared to the marketed product in 5 h.
CONCLUSION
Owing to the significantly improved drug solubility, in vitro release and better antibacterial activity, it can be assumed that CFX-loaded SEDDS might lead to an increased bioavailability and antibacterial activity, possibly leading to improved therapeutic effectiveness.
Topics: Cefixime; Surface-Active Agents; Emulsions; Drug Delivery Systems; Solubility; Drug Liberation; Administration, Oral; Anti-Bacterial Agents; Permeability; Biological Availability; Particle Size
PubMed: 36985803
DOI: 10.3390/molecules28062827 -
International Journal of Pharmaceutics Jun 2023Propofol is the preferred anaesthetic for induction and maintenance of sedation in critically ill mechanically ventilated COVID-19 patients. However, during the outbreak...
Propofol is the preferred anaesthetic for induction and maintenance of sedation in critically ill mechanically ventilated COVID-19 patients. However, during the outbreak of the COVID-19 pandemic, regular supply chains could not keep up with the sudden increase in global demand, causing drug shortages. Propofol is formulated as an oil-in-water emulsion which is administered intravenously. This study explores the extemporaneous preparation of a propofol emulsion without specialized manufacturing equipment to temporally alleviate such shortages. A commercially available lipid emulsion (IVLE, SMOFlipid 20 %), intended for parenteral nutrition, was used to create a propofol loaded nanoemulsion via addition of liquid propofol drug substance and subsequent mixing. Critical quality attributes such as mean droplet size and the volume-weighted percentage of large-diameter (>5µm) droplets were studied. The evolution of droplet size and propofol distribution was monitored in situ and non-destructively, maintaining sterility, using Spatially Resolved Dynamic Light Scattering and Near Infrared Spectroscopy, respectively. Using response surface methodology, an optimum was found for a 4 % w/v propofol formulation with a ∼15 min mixing time in a flask shaker at a 40° shaking angle. This study shows that extemporaneous compounding is a viable option for emergency supply of propofol drug product during global drug shortages.
Topics: Humans; Propofol; Emulsions; Pandemics; COVID-19; Parenteral Nutrition
PubMed: 37061210
DOI: 10.1016/j.ijpharm.2023.122960 -
International Journal of Nanomedicine 2019The aims of this study were to prepare a baicalein self-microemulsion with baicalein-phospholipid complex as the intermediate (BAPC-SMEDDS) and to compare its effects...
PURPOSE
The aims of this study were to prepare a baicalein self-microemulsion with baicalein-phospholipid complex as the intermediate (BAPC-SMEDDS) and to compare its effects with those of conventional baicalein self-microemulsion (CBA-SMEDDS) on baicalein oral absorption and lymphatic transport.
METHODS
Two SMEDDS were characterized by emulsifying efficiency, droplet size, zeta potential, cloud point, dilution stability, physical stability, and in vitro release and lipolysis. Different formulations of 40 mg/kg baicalein were orally administered to Sprague-Dawley rats to investigate their respective bioavailabilities. The chylomicron flow blocking rat model was used to evaluate their lymphatic transport.
RESULTS
The droplet sizes of BAPC-SMEDDS and CBA-SMEDDS after 100x dilution were 9.6±0.2 nm and 11.3±0.4 nm, respectively. In vivo experiments indicated that the relative bioavailability of CBA-SMEDDS and BAPC-SMEDDS was 342.5% and 448.7% compared to that of free baicalein (BA). The AUC and C of BAPC-SMEDDS were 1.31 and 1.87 times higher than those of CBA-SMEDDS, respectively. The lymphatic transport study revealed that 81.2% of orally absorbed BA entered the circulation directly through the portal vein, whereas approximately 18.8% was transported into the blood via lymphatic transport. CBA-SMEDDS and BAPC-SMEDDS increased the lymphatic transport ratio of BA from 18.8% to 56.2% and 70.2%, respectively. Therefore, self-microemulsion not only significantly improves oral bioavailability of baicalein, but also increases the proportion lymphatically transported. This is beneficial to the direct interaction of baicalein with relevant immune cells in the lymphatic system and for proper display of its effects.
CONCLUSION
This study demonstrates the oral absorption and lymphatic transport characteristics of free baicalein and baicalein SMEDDS with different compositions. This is of great significance to studies on lymphatic targeted delivery of natural immunomodulatory compounds.
Topics: Absorption, Physiological; Administration, Oral; Animals; Biological Availability; Drug Compounding; Drug Delivery Systems; Emulsions; Flavanones; Lymphatic System; Male; Phospholipids; Rats; Rats, Sprague-Dawley; Solubility
PubMed: 31564878
DOI: 10.2147/IJN.S214883 -
BMJ Case Reports May 2020A 26-year-old woman presented after an intentional ingestion of 20 g of caffeine. She suffered a profound respiratory alkalosis with metabolic acidosis, hypokalaemia...
A 26-year-old woman presented after an intentional ingestion of 20 g of caffeine. She suffered a profound respiratory alkalosis with metabolic acidosis, hypokalaemia and sustained polymorphic ventricular tachycardia. She was treated with intravenous intralipid and haemodialysis, and her arrhythmia was controlled using magnesium sulphate. Once invasively ventilated and unable to hyperventilate the patient became acidotic and required intravenous bicarbonate to correct her acid-base status. Two days following the overdose the patient was extubated, haemodialysis was stopped and norepinephrine was weaned off. The patient was discharged after a further 7 days. Serial caffeine levels were taken during this patient's care; the highest measured caffeine concentration 7 hours after ingestion was 147.1 mg/L. The known lethal dose of caffeine is 80 mg/L. Intralipid and haemodialysis represent a new and viable treatment in life-threatening caffeine overdose. Intravenous magnesium may terminate unstable arrhythmias in caffeine-poisoned patients.
Topics: Acidosis; Adult; Anti-Arrhythmia Agents; Caffeine; Drug Overdose; Emulsions; Fat Emulsions, Intravenous; Female; Humans; Hypokalemia; Magnesium Sulfate; Phospholipids; Renal Dialysis; Soybean Oil; Suicide, Attempted; Tachycardia, Ventricular
PubMed: 32414776
DOI: 10.1136/bcr-2020-234256 -
Analytical Chemistry Jan 2023Water-in-oil droplet microfluidics promises capacity for high-throughput single-cell antimicrobial susceptibility assays and investigation of drug resistance mechanisms....
Water-in-oil droplet microfluidics promises capacity for high-throughput single-cell antimicrobial susceptibility assays and investigation of drug resistance mechanisms. Every droplet must serve as an isolated environment with a controlled antibiotic concentration in such assays. While technologies for generation, incubation, screening, and sorting droplets mature, predictable retention of active molecules inside droplets remains a major outstanding challenge. Here, we analyzed 36 descriptors of the antibiotic molecules against experimental results on the cross-talk of antibiotics in droplets. We show that partition coefficient and fractional polar surface area are the key physicochemical properties that predict antibiotic retention. We verified the prediction by monitoring growth inhibition by antibiotic-loaded neighboring droplets. Our experiments also demonstrate that transfer of antibiotics between droplets is concentration- and distance-dependent. Our findings immediately apply to designing droplet antibiotic assays and give deeper insight into the retention of small molecules in water-in-oil emulsions.
Topics: Water; Microfluidics; Technology; Emulsions; High-Throughput Screening Assays
PubMed: 36598882
DOI: 10.1021/acs.analchem.2c04644