Search

Malaria is one of the most prevalent parasitic diseases and the foremost cause of morbidity in the tropical regions of the world. Strategies for the efficient management of this parasitic infection include adequate treatment with anti-malarial therapeutics and vaccination. However, the emergence and spread of resistant strains of malaria parasites to the majority of presently used anti-malarial medications, on the other hand, complicates malaria treatment. Other shortcomings of anti-malarial drugs include poor aqueous solubility, low permeability, poor bioavailability, and non-specific targeting of intracellular parasites, resulting in high dose requirements and toxic side effects. To address these limitations, liposome-based nanotechnology has been extensively explored as a new solution in malaria management. Liposome technology improves anti-malarial drug encapsulation, bioavailability, target delivery, and controlled release, resulting in increased effectiveness, reduced resistance progression, and fewer adverse effects. Furthermore, liposomes are exploited as immunological adjuvants and antigen carriers to boost the preventive effectiveness of malaria vaccine candidates. The present review discusses the findings from studies conducted over the last 40 years (1980–2020) using in vitro and in vivo settings to assess the prophylactic and curative anti-malarial potential of liposomes containing anti-malarial agents or antigens. This paper and the discussion herein provide a useful resource for further complementary investigations and may pave the way for the research and development of several available and affordable anti-malarial-based liposomes and liposomal malaria vaccines by allowing a thorough evaluation of liposomes developed to date for the management of malaria. [ABSTRACT FROM AUTHOR]

Selective drug delivery to inflamed tissues is of widespread interest for the treatment of inflammatory bowel disease (IBD). Because a lack of physiological lipids has been described in patients suffering IBD, and some lipids present immunomodulatory properties, we hypothesize that the combination of lipids and anti-inflammatory drugs together within a nanocarrier may be a valuable strategy for overcoming IBD. In the present study, we investigated and compared the in vitro and in vivo efficacy of three lipid-based nanocarriers containing curcumin (CC) as an anti-inflammatory drug for treating IBD in a murine DSS-induced colitis model. These nanocarriers included self-nanoemulsifying drug delivery systems (SNEDDS), nanostructured lipid carriers (NLC) and lipid core-shell protamine nanocapsules (NC). In vitro , a 30-fold higher CC permeability across Caco-2 cell monolayers was obtained using NC compared to SNEDDS (NC > SNEDDS > NLC and CC suspension). The CC SNEDDS and CC NLC but not the CC NC or CC suspension significantly reduced TNF-α secretion by LPS-activated macrophages (J774 cells). In vivo , only CC NLC were able to significantly decrease neutrophil infiltration and TNF-α secretion and, thus, colonic inflammation. Our results show that a higher CC permeability does not correlate with a higher efficacy in IBD treatment, which suggests that lipidic nanocarriers exhibiting increased CC retention at the intestinal site, rather than increased CC permeability are efficient treatments of IBD. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Malaria is the most prevalent parasitic disease and the foremost cause of morbidity and mortality in the Democratic Republic of Congo. For the management of this disease, a large Congolese population recourses to traditional medicinal plants. To date the efficacy and safety of many of these plants have been validated scientifically in rodent malaria models. In order to generate scientific evidence of traditional remedies used in the Democratic Republic of Congo for the management of malaria, and show the potential of Congolese plants as a major source of antimalarial drugs, this review highlights the antiplasmodial and toxicological properties of the Congolese antimalarial plants investigated during the period of 1999–2014. In doing so, a useful resource for further complementary investigations is presented. Furthermore, this review may pave the way for the research and development of several available and affordable antimalarial phytomedicines. Materials and methods In order to get information on the different studies, a Google Scholar and PubMed literature search was performed using keywords (malaria, Congolese, medicinal plants, antiplasmodial/antimalarial activity, and toxicity). Data from non-indexed journals, Master and Doctoral dissertations were also collected. Results Approximately 120 extracts and fractions obtained from Congolese medicinal plants showed pronounced or good antiplasmodial activity. A number of compounds with interesting antiplasmodial properties were also isolated and identified. Some of these compounds constituted new scaffolds for the synthesis of promising antimalarial drugs. Interestingly, most of these extracts and compounds possessed high selective activity against Plasmodium parasites compared to mammalian cells. The efficacy and safety of several plant-derived products was confirmed in mice, and a good correlation was observed between in vitro and in vivo antimalarial activity. The formulation of several plant-derived products also led to some clinical trials and license of three plant-derived drugs (Manalaria ® , Nsansiphos ® , and Quinine Pharmakina ® ). Conclusion The obtained results partly justify and support the use of various medicinal plants to treat malaria in folk medicine in the Democratic Republic of Congo. Antimalarial plants used in Congolese traditional medicine represent an important source for the discovery and development of new antimalarial agents. However, in order to ensure the integration of a larger number of plant-derived products in the Congolese healthcare system, some parameters and trends should be considered in further researches, in agreement with the objectives of the “Traditional Medicine Strategy” proposed by the World Health Organization in 2013. These include evaluation of geographical and seasonal variation, investigation of reproductive biology, assessment of prophylactic antimalarial activity, evaluation of natural products as adjuvant antioxidant therapy for malaria, development of plant-based combination therapies and monitoring of herbal medicines in pharmacovigilance systems. [ABSTRACT FROM AUTHOR]

Highlights: [•] A LC method for simultaneous analysis of curcumin and β-arteether is described. [•] The design of experiment and the design space were used to optimize the method. [•] The LC method was validated using the accuracy profile as decision tool. [•] The method was applied for analysis of curcumin and β-arteether lipid formulations. [ABSTRACT FROM AUTHOR]

Abstract: Curcumin (CC), a potential antimalarial drug, has poor water solubility, stability and oral bioavailability. To circumvent these pitfalls, lipid-based drug delivery systems (LBDDSs) with a high CC loading (30mg/g) were formulated. In a biorelevant gastric medium, CC-LBDDSs formed particle sizes in the range of 30–40nm. During in vitro lipolysis, 90–95% of the CC remained solubilized, whereas 5–10% of the CC precipitated as an amorphous solid, with a high rate of re-dissolution in a biorelevant intestinal medium. The transport of the CC-LBDDS across Caco-2 monolayers was enhanced compared with the transport of free drug because of the increased CC solubility. In Plasmodium berghei-infected mice, modest antimalarial efficacy was observed following oral treatment with CC-LBDDSs. However, the combination therapy of CC-LBDDS with a subtherapeutic dose of β-arteether-LBDDS provided an increase in protection and survival rate that was associated with a significant delay in recrudescence. These findings suggest that the combination of oral CC and β-arteether lipid-based formulations may constitute a promising approach for the treatment of malaria. [Copyright &y& Elsevier]

Abstract: β-Arteether, an effective artemisinin derivative, is used in the treatment of malaria but available only as an intramuscular injection. The objective of this work was to develop lipid-based formulations for oral administration of β-arteether. Self-emulsifying drug delivery systems (SEDDSs) of low cost and with accessible excipients (groundnut or sesame oil, Maisine 35-1, Tween 80 or Cremophor EL, and absolute ethanol) were formulated. In 250ml of simulated gastric medium, 1g of these SEDDS solubilized the daily dose of β-arteether and formed lipid droplets of average size 80–250nm. No toxicity against Caco-2 intestinal cells was observed. Using a mouse model, the efficacy of these arteether lipid formulations against Plasmodium berghei was evaluated. A daily dose of 24mg/kg for 4days led to complete cure for more than 45days in 100% of treated mice and had an antimalarial efficacy comparable to that of an intramuscular oily solution of arteether and significantly higher than that of an oily solution of β-arteether given orally at the same dose. In conclusion, lipid-based drug delivery systems constitute a promising approach for the oral administration of β-arteether. [Copyright &y& Elsevier]

Diabetes is a metabolic pathology with chronic high blood glucose levels that occurs when the pancreas does not produce enough insulin or the body does not properly use the insulin it produces. Diabetes management is a puzzle and focuses on a healthy lifestyle, physical exercise, and medication. Thus far, the condition remains incurable; management just helps to control it. Its medical treatment is expensive and is to be followed for the long term, which is why people, especially from low-income countries, resort to herbal medicines. However, many active compounds isolated from plants (phytocompounds) are poorly bioavailable due to their low solubility, low permeability, or rapid elimination. To overcome these impediments and to alleviate the cost burden on disadvantaged populations, plant nanomedicines are being studied. Nanoparticulate formulations containing antidiabetic plant extracts or phytocompounds have shown promising results. We herein aimed to provide an overview of the use of lipid- and inorganic-based nanoparticulate delivery systems with plant extracts or phytocompounds for the treatment of diabetes while highlighting their advantages and limitations for clinical application. The findings from the reviewed works showed that these nanoparticulate formulations resulted in high antidiabetic activity at low doses compared to the corresponding plant extracts or phytocompounds alone. Moreover, it was shown that nanoparticulate systems address the poor bioavailability of herbal medicines, but the lack of enough preclinical and clinical pharmacokinetic and/or pharmacodynamic trials still delays their use in diabetic patients. [ABSTRACT FROM AUTHOR]

Antimicrobial natural polymer film with silver nanoparticles (AgNPs) biosynthesized using aqueous plant root extracts as reducing capping agents and for film formatting show extensive applicability for pathogenic microorganism problems. The formation of AgNPs was confirmed by transmission electron microscopy (TEM) and scanning electron microscopy–energy-dispersive spectroscopy (SEM–EDS) techniques. The antimicrobial activity of biofilm with green AgNPs was analysed by inhibiting the growth of Gram-negative and Gram-positive bacteria culture using the Kirby–Bauer disk diffusion susceptibility test. Total phenolic content and antioxidant activity were slightly higher in aqueous extracts of Sym. Radix than in Sym. Radix/AgNPs. The antimicrobial effect of polymer film/AgNPs against selected test bacteria cultures was substantially more robust than with pure film. Pictures of AgNPs obtained by TEM revealed the presence of spherical-shaped nano-objects with an average size 27.45 nm. SEM–EDS studies confirmed the uniform distribution of metal nanoparticles throughout the biopolymeric matrix. Morphological studies of the surface showed that the obtained surface of the films was even, without holes or other relief irregularities. These apparent Symphyti radix polymer film/AgNPs' biological functions could provide a platform for fighting pathogenic bacteria in the era of multi-drug resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: Mosquitoes are the carrier of pathogens that cause common human diseases such as malaria, Dengue, Chikungunya, yellow fever, Zika, and West Nile. The use of chemical and biological insecticides is among the key control tools for reducing mosquito populations at different life stages (i.e., eggs, larvae, pupae, and adults). The weaknesses of these tools, especially those with chemicals, are the high cost of production, and their negative effects on other beneficial organisms such as bees and water-dwelling invasive species. Thus, researchers and academics are searching for new safe and environmentally friendly forms of insecticides. Of late, green synthesized plant-based metallic nanoparticles have attracted great interest as an alternative to traditional insecticides. Typically using metal salts in combination with aqueous plant extracts, the synthesis of these nanoparticles is eco-friendly and relatively cheap. This review aims to report on the currently available knowledge on the development of green synthesized metallic nanoparticles and their performance as repellent, ovicidal, larvicidal, pupicidal, and adulticidal agents against different mosquito species. Mosquitoes act as vectors of pathogens that cause most life-threatening diseases, such as malaria, Dengue, Chikungunya, Yellow fever, Zika, West Nile, Lymphatic filariasis, etc. To reduce the transmission of these mosquito-borne diseases in humans, several chemical, biological, mechanical, and pharmaceutical methods of control are used. However, these different strategies are facing important and timely challenges that include the rapid spread of highly invasive mosquitoes worldwide, the development of resistance in several mosquito species, and the recent outbreaks of novel arthropod-borne viruses (e.g., Dengue, Rift Valley fever, tick-borne encephalitis, West Nile, yellow fever, etc.). Therefore, the development of novel and effective methods of control is urgently needed to manage mosquito vectors. Adapting the principles of nanobiotechnology to mosquito vector control is one of the current approaches. As a single-step, eco-friendly, and biodegradable method that does not require the use of toxic chemicals, the green synthesis of nanoparticles using active toxic agents from plant extracts available since ancient times exhibits antagonistic responses and broad-spectrum target-specific activities against different species of vector mosquitoes. In this article, the current state of knowledge on the different mosquito control strategies in general, and on repellent and mosquitocidal plant-mediated synthesis of nanoparticles in particular, has been reviewed. By doing so, this review may open new doors for research on mosquito-borne diseases. [ABSTRACT FROM AUTHOR]

Skin delivery is an exciting and challenging field. It is a promising approach for effective drug delivery due to its ease of administration, ease of handling, high flexibility, controlled release, prolonged therapeutic effect, adaptability, and many other advantages. The main associated challenge, however, is low skin permeability. The skin is a healthy barrier that serves as the body's primary defence mechanism against foreign particles. New advances in skin delivery (both topical and transdermal) depend on overcoming the challenges associated with drug molecule permeation and skin irritation. These limitations can be overcome by employing new approaches such as lipid nanosystems. Due to their advantages (such as easy scaling, low cost, and remarkable stability) these systems have attracted interest from the scientific community. However, for a successful formulation, several factors including particle size, surface charge, components, etc. have to be understood and controlled. This review provided a brief overview of the structure of the skin as well as the different pathways of nanoparticle penetration. In addition, the main factors influencing the penetration of nanoparticles have been highlighted. Applications of lipid nanosystems for dermal and transdermal delivery, as well as regulatory aspects, were critically discussed. [ABSTRACT FROM AUTHOR]

Silver nanoparticles (AgNPs) biosynthesized using aqueous medical plant extracts as reducing and capping agents show multiple applicability for bacterial problems. The aim of this study was to expand the boundaries on AgNPs using a novel, low-toxicity, and cost-effective alternative and green approach to the biosynthesis of metallic NPs using Calendula officinalis (Calendula) and Hyssopus officinalis (Hyssopus) aqueous extracts. The formation of AgNPs was confirmed by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and energy-dispersive spectroscopy (EDS) techniques. The effectiveness of biosynthesized AgNPs in quenching free radicals and inhibiting the growth of Gram-positive and Gram-negative microorganisms was supported by in vitro antioxidant activity assay methods and using the Kirby–Bauer disk diffusion susceptibility test, respectively. The elucidated antimicrobial and antioxidative activities of medical plant extracts were compared with data from the engineered biosynthetic AgNPs. The antimicrobial effect of engineered AgNPs against selected test cultures was found to be substantially stronger than for plant extracts used for their synthesis. The analysis of AgNPs by TEM revealed the presence of spherical-shaped nano-objects. The size distribution of AgNPs was found to be plant-type-dependent. The smaller AgNPs were obtained with Hyssopus extract (with a size range of 16.8 ± 5.8 nm compared to 35.7 ± 4.8 nm from Calendula AgNPs). The AgNPs' presumably inherited biological functions of Hyssopus and Calendula medical plants can provide a platform to combat pathogenic bacteria in the era of multi-drug resistance. [ABSTRACT FROM AUTHOR]

Metallic nanoparticles (MNPs) produced by green synthesis using plant extracts have attracted huge interest in the scientific community due to their excellent antibacterial, antifungal and antibiofilm activities. To evaluate these pharmacological properties, several methods or protocols have been successfully developed and implemented. Although these protocols were mostly inspired by the guidelines from national and international regulatory bodies, they suffer from a glaring absence of standardization of the experimental conditions. This situation leads to a lack of reproducibility and comparability of data from different study settings. To minimize these problems, guidelines for the antimicrobial and antibiofilm evaluation of MNPs should be developed by specialists in the field. Being aware of the immensity of the workload and the efforts required to achieve this, we set out to undertake a meticulous literature review of different experimental protocols and laboratory conditions used for the antimicrobial and antibiofilm evaluation of MNPs that could be used as a basis for future guidelines. This review also brings together all the discrepancies resulting from the different experimental designs and emphasizes their impact on the biological activities as well as their interpretation. Finally, the paper proposes a general overview that requires extensive experimental investigations to set the stage for the future development of effective antimicrobial MNPs using green synthesis. [ABSTRACT FROM AUTHOR]

Nano-scaled particles have been found to preferentially accumulate in inflamed regions. Local delivery of anti-inflammatory drugs loaded in nanoparticles to the inflamed colonic site is of great interest for inflammatory bowel disease (IBD) treatment. Curcumin (CC) is an anti-inflammatory local agent, which presents poor ADME properties. Hence, we evaluated, both in vitro and in vivo , the local delivery of CC using pH-sensitive polymeric nanoparticles (NPs) combining both poly(lactide- c o-glycolide) acid (PLGA) and a polymethacrylate polymer (Eudragit ® S100). CC-NPs significantly enhanced CC permeation across Caco-2 cell monolayers when compared to CC in suspension. CC-NPs significantly reduced TNF-α secretion by LPS-activated macrophages (J774 cells). In vivo , CC-NPs significantly decreased neutrophil infiltration and TNF-α secretion while maintaining the colonic structure similar to the control group in a murine DSS-induced colitis model. Our results support the use of nanoparticles made of PLGA and Eudragit ® S100 combination for CC delivery in IBD treatment. [ABSTRACT FROM AUTHOR]

Abstract: Wound healing is a complex process involving many interdependent and overlapping sequences of physiological actions. The application of exogenous lactate released from poly (lactic-co-glycolic acid) (PLGA) polymer accelerated angiogenesis and wound healing processes. Curcumin is a well-known topical wound healing agent for both normal and diabetic-impaired wounds. Hence, we hypothesized that the PLGA nanoparticles encapsulating curcumin could much potentially accelerate the wound healing. In a full thickness excisional wound healing mouse model, PLGA–curcumin nanoparticles showed a twofold higher wound healing activity compared to that of PLGA or curcumin. Histology and RT-PCR studies confirmed that PLGA–curcumin nanoparticles exhibited higher re-epithelialization, granulation tissue formation and anti-inflammatory potential. PLGA nanoparticles offered various benefits for the encapsulated curcumin like protection from light degradation, enhanced water solubility and showed a sustained release of curcumin over a period of 8days. In conclusion, we demonstrated the additive effect of lactic acid from PLGA and encapsulated curcumin for the active healing of wounds. [Copyright &y& Elsevier]

[Display omitted] Zinc is one of the most studied trace elements, commonly used as supplement in diabetes treatment. By its involvement in the synthesis, secretion of insulin, promotion of insulin sensitivity and its multiple enzymatic functions it is known to contribute to reduce hyperglycemia. Researchers have shown that zinc administered under the form of zinc oxide nanoparticles (ZnONPs) is more effective than under its ionic form. Studies evaluating the antihyperglycemic activity of these nanocarriers include both ZnONPs synthesised using plants (i.e. green synthesized) or chemically synthesized. The present work aims to compare green synthesized ZnONPs with the marketed chemically synthesized ones. Green ZnONPs were synthesized using the aqueous extract of the stem bark of the medicinal plant Panda oleosa and zinc nitrate hexahydrate. Both nanocarriers were compared in terms of optical properties, morphology, composition, chemical functions, resistance to oxidation, in vivo antihyperglycemic activity via oral glucose tolerance test (OGTT) and pharmacokinetics in relation to zinc in C57BL/6J mice. A UV absorption peak was observed at 354 nm and 374 nm for the green and marketed ZnONPs, respectively. The shape and hydrodynamic diameters were anisotropic and of 228.8 ± 3.0 nm for the green ZnONPs and spherical and of 225.6 ± 0.9 nm for the marketed ZnONPs. Phenolic compounds accounted for 2.58 ± 0.04% of the green ZnONPs and allowed them to be more stable and unaffected by an oxidizing agent during the experiment, while the marketed chemically synthesized ZnONPs aggregated with or without contact with an oxidizing agent. No significant differences were observed on the amounts of zinc absorbed when comparing green ZnONPs, chemically synthesized ZnONPs and zinc sulfate in a pharmacokinetics study in normoglycemic mice. When evaluating the in vivo hypoglycemic activity of the nanocarriers in obese/diabetic mice, green synthesized ZnONPs displayed a significant hypoglycemic effect compared with the chemically synthesized nanoparticles following an OGTT. Altogether, these data indicate that phytocompounds, as catechin derivatives and polyphenols, attached to the green synthesized ZnONPs' surface, could contribute to their hypoglycemic activity. The comparison thus demonstrated that green synthesized ZnONPs are significantly more efficient than chemically ones at reducing hyperglycemia regardless of their absorption. [ABSTRACT FROM AUTHOR]

Approximately one third of newly discovered drug molecules show insufficient water solubility and therefore low oral bio-availability. Self-nano-emulsifying drug-delivery systems (SNEDDSs) are one of the emerging strategies developed to tackle the issues associated with their oral delivery. SNEDDSs are composed of an oil phase, surfactant, and cosurfactant or cosolvent. SNEDDSs characteristics, their ability to dissolve a drug, and in vivo considerations are determinant factors in the choice of SNEDDSs excipients. A SNEDDS formulation can be optimized through phase diagram approach or statistical design of experiments. The characterization of SNEDDSs includes multiple orthogonal methods required to fully control SNEDDS manufacture, stability, and biological fate. Encapsulating a drug in SNEDDSs can lead to increased solubilization, stability in the gastro-intestinal tract, and absorption, resulting in enhanced bio-availability. The transformation of liquid SNEDDSs into solid dosage forms has been shown to increase the stability and patient compliance. Supersaturated, mucus-permeating, and targeted SNEDDSs can be developed to increase efficacy and patient compliance. Self-emulsification approach has been successful in oral drug delivery. The present review gives an insight of SNEDDSs for the oral administration of both lipophilic and hydrophilic compounds from the experimental bench to marketed products. [ABSTRACT FROM AUTHOR]

[Display omitted] Zinc oxide nanoparticles (ZnONPs) have shown antidiabetic activity in multiple studies and can be produced by different plant-mediated ("green") methods. This study aimed to compare ZnONPs prepared via different "green" approaches (heating at high temperatures (400 °C) vs. low temperature (70 °C)). The low temperature method involved addition of suspending agents (Tween 80 or gum arabic) and pH variations followed by lyophilization. The study evaluated the hypoglycemic potential of ZnONPs with the best properties (quantity of capped agents and stability) compared to the plant extract per se. The ZnONP synthesis involved a mixture of zinc nitrate hexahydrate as the zinc precursor and a plant extract with high antioxidant activity as the capping agent supplier. The results of the studies showed that the procedure using high-temperature heating resulted in almost uncapped nanoparticles with phytocompounds (0.01 % of phenolic compounds) and nanoparticle sizes larger than 300 nm. The low-temperature method produced ZnONPs with high retention of capping agents (92.90 % of phenolic compounds) and a size of approximately 200 nm. The use of Tween 80 with pH adjustment between 9 and 10 resulted in more stable nanoparticles than with gum arabic. These nanoparticles prepared with Tween 80, exhibited a pronounced in vivo antihyperglycemic activity at a much lower dose (10 mg ZnO/kg capped by 0.31 mg phenolic compounds per kg) than the extracts alone (400 mg extract/kg) following an oral glucose tolerance test. These results demonstrated that green-synthesized ZnONPs with a high retention rate of phytochemicals can induce antihyperglycemic effects at a low dose. [ABSTRACT FROM AUTHOR]

Background: Supra-nutritional doses of curcumin, derived from the spice Curcuma longa, have been proposed as a potential treatment of inflammation and metabolic disorders related to obesity. The aim of the present study was to test whether Curcuma longa extract rich in curcumin and associated with white pepper (Curcuma-P®), at doses compatible with human use, could modulate systemic inflammation in diet-induced obese mice. We questioned the potential relevance of changes in adiposity and gut microbiota in the effect of Curcuma-P® in obesity. Methodology/Principal Findings: Mice were fed either a control diet (CT), a high fat (HF) diet or a HF diet containing Curcuma longa extract (0.1 % of curcumin in the HF diet) associated with white pepper (0.01 %) for four weeks. Curcumin has been usually combined with white pepper, which contain piperine, in order to improve its bioavailability. This combination did not significantly modify body weight gain, glycemia, insulinemia, serum lipids and intestinal inflammatory markers. Tetrahydrocurcumin, but not curcumin accumulated in the subcutaneous adipose tissue. Importantly, the co-supplementation in curcuma extract and white pepper decreased HF-induced proinflammatory cytokines expression in the subcutaneous adipose tissue, an effect independent of adiposity, immune cells recruitment, angiogenesis, or modulation of gut bacteria controlling inflammation. Conclusions/Significance: These findings support that nutritional doses of Curcuma longa, associated with white pepper, is able to decrease inflammatory cytokines expression in the adipose tissue and this effect could be rather linked to a direct effect of bioactive metabolites reaching the adipose tissue, than from changes in the gut microbiota composition. [ABSTRACT FROM AUTHOR]

Low aqueous solubility and poor oral bioavailability are limiting factors in the oral delivery of voxelotor, an antisickling agent. To overcome these limitations, a voxelotor self-nanoemulsifying drug delivery system was developed. Various oils, surfactants, and cosurfactants were screened for their solubilization potential for the drug. The area of nanoemulsification was identified using a ternary phase diagram. An experimental mixture design and a desirability function were applied to select SNEDDSs that contain a maximum amount of lipids and a minimum amount of surfactant, and that possess optimal emulsification properties (i.e., droplet sizes, polydispersity index (PDI), emulsification time, and transmittance percentage). The optimized SNEDDS formulation was evaluated for the self-emulsifying time (32 s), droplet size (35 nm), and zeta potential (−8 mV). In vitro dissolution studies indicated a 3.1-fold improvement in drug solubility from the optimized SNEDDS over pure drug powder. After 60 min of in vitro lipolysis, 88% of the voxelotor loaded in the SNEDDS remained in the aqueous phase. Cytotoxicity evaluation, using Caco-2 cells, indicated the safety of the formulation at 0.9 mg/mL. The transport of the voxelotor SNEDDS across Caco-2 monolayers was significantly enhanced compared to that of the free drug. Compared to the drug suspension, the developed SNEDDS enhanced the oral bioavailability (1.7-fold) of voxelotor in rats. The results suggest that further development of SNEDDSs for the oral delivery of voxelotor is needed. [ABSTRACT FROM AUTHOR]

Senicapoc (SEN), a potent antisickling agent, shows poor water solubility and poor oral bioavailability. To improve the solubility and cell permeation of SEN, self-nanoemulsifying drug delivery systems (SNEDDSs) were developed. Capryol PGMC®, which showed the highest solubilization capacity, was selected as the oil. The self-emulsification ability of two surfactants, viz., Cremophor-EL® and Tween® 80, was compared. Based on a solubility study and ternary phase diagrams, three optimized nanoemulsions with droplet sizes less than 200 nm were prepared. An in vitro dissolution study demonstrated the superior performance of the SNEDDS over the free drug. During in vitro lipolysis, 80% of SEN loaded in the SNEDDS remained solubilized. An in vitro cytotoxicity study using the Caco-2 cell line indicated the safety of the formulations at 1 mg/mL. The transport of SEN-SNEDDSs across Caco-2 monolayers was enhanced 115-fold (p < 0.01) compared to that of the free drug. According to these results, SNEDDS formulations could be promising tools for the oral delivery of SEN. [ABSTRACT FROM AUTHOR]