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Drug delivery to ocular tissues is mainly hindered by anatomical and physiological barriers that diminish their bioavailability. In this work, layered double hydroxides (LDHs) intercalated with non-steroidal anti-inflammatory drugs (NSAIDs; ibuprofen, ketoprofen, and ketorolac) were incorporated into carboxymethylcellulose (CMC) dispersions with the aim of adjusting their rheological properties, producing sustained release, and inducing mucoadhesive properties. Pure NSAID-intercalated LDHs (LDH-NSAID) with high drug loading were obtained. The obtained particles showed high aggregation and positive surface charges, which allowed interaction with the negatively charged groups of CMC. Isotonic 1% CMC and 1% LDH-NSAID (w/w) dispersions behaved as viscous, shear-thinning fluids, although a stronger interaction with ketoprofen led to more gel-like behavior. Also, CMC/LDH-NSAID dispersions exhibited a more sustained drug release than that achieved with analogous formulations containing pure drugs, and the modeling of the profile indicated that the release rate was mainly determined by the anion exchange of the intercalated NSAID. Finally, the formulations showed strong mucoadhesion capacity, as they produce significant changes in the zeta potential of mucin dispersions. Further optimization of the particle size and surface properties of the particles is required to modulate the release profile and to enhance the rheological properties of these CMC/LDH-based formulations. [ABSTRACT FROM AUTHOR]

Abstract: In order to enhance the ocular bioavailability of acetazolamide (ACZ), a multicomponent complex with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and triethanolamine (TEA) was prepared to be applied topically. In vitro corneal permeation across isolated rabbit cornea of proposed ACZ formulations and the marketed AZOPT® formulation (1% w/v brinzolamide) was studied. Formulations were also tested for their effect on the intraocular pressure (IOP) in rabbits. 1H- and 13C-NMR experiments were undertaken to verify the real inclusion of ACZ in the ACZ–HP-ß-CD–TEA multicomponent complex. The binding of ACZ to HP-ß-CD in the presence of TEA is described. The increase of TEA concentration decreases the apparent equilibrium constant for the ACZ–HP-ß-CD complex. The ternary system ACZ–HP-ß-CD–TEA seemed to be able to reduce IOP in about 30%. This effect was sustained for 4 h after instillation. In vitro corneal permeation studies demonstrated that the ACZ permeation was increased. RMN experiments indicated that TEA can weaken the association between ACZ and HP-ß-CD increasing the drug ocular hypotensive effect by increasing the free drug available for absorption. Our formulations were considered practically non-irritant. These results indicate that the ternary system ACZ–HP-ß-CD–TEA might be a useful tool for formulating aqueous ACZ eye drop solutions. [Copyright &y& Elsevier]

Currently, biological drug therapy for ocular angiogenesis treatment is based on the administration of anti-VEGF agents via intravitreal route. The molecules approved with this purpose for ocular use include pegaptanib, ranibizumab, and aflibercept, whereas bevacizumab is commonly off-label used in the clinical practice. The schedule dosage involves repeated intravitreal injections of anti-VEGF agents to achieve and maintain effective concentrations in retina and choroids, which are administrated as solutions form. In this review article, we describe the features of different anti-VEGF agents, major challenges for their ocular delivery and the nanoparticles in development as delivery system of them. In this way, several polymeric and lipid nanoparticles are explored to load anti-VEGF agents with the aim of achieving sustained drug release and thus, minimize the number of intravitreal injections required. The main challenges were focused in the loading the molecules that maintain their bioactivity after their release from nanoparticulate system, followed the evaluation of them through studies of formulation stability, pharmacokinetic, and efficacy in in vitro and in vivo models. The analysis was based on the information published in peer-reviewed published papers relevant to anti-VEGF treatments and nanoparticles developed as ocular antiVEGF delivery system. [ABSTRACT FROM AUTHOR]

Sustainable corn starch nanoparticles were prepared using media milling to stabilize omega-3-rich Pickering emulsions based on chia oil. The milling conditions were as follows: 24 h (milling time), 0.4–0.6 mm (bead diameter), 1600 rpm (impeller speed), 30% (volume occupied by the grinding media), 7% w/v (starch concentration), and 0, 0.07 and 1% w/v of sodium dodecyl sulfate (SDS). Nanosuspensions containing 7% w/v of starch and the three concentrations of SDS were filtered, centrifuged, homogenized, and spray-dried to obtain redispersible powders. The particle size ranges were 2288 ± 211, 385 ± 21, and 278 ± 11 nm with 0, 0.07 and 1% w/v of SDS, respectively. The most stable backscattering profiles obtained during a period of one week were observed with 0.07 and 1% w/v of SDS. Therefore, the surface dilatational rheology of these particles adsorbed at chia oil/water interfaces was studied. A rapid decrease in the interfacial tension within 1 h was obtained with 1% w/v of SDS (down to 3 mN/m). Moreover, the most stable particle size after redispersion was obtained with the highest concentration of SDS. Finally, Pickering emulsions were prepared, and significant coalescence was observed with 0 and 0.07% w/v of SDS (within a few minutes). Nonetheless, in the presence of 1% w/v of SDS, oil droplets showed mean diameters and polydispersity indexes of 280.13 ± 4.60 nm and 0.35 ± 0.02, respectively, with no significant variations during storage for around 1 month. The results show that wet-stirred media milling can be applied to produce sustainable, new food-grade starch nanoparticles able to deliver bioactive compounds from chia oil. [ABSTRACT FROM AUTHOR]

Over the past few years, there has been increasing attention to the design of new drug delivery systems based on milk proteins due to their excellent functional properties. In this study, we report a new approach for preparing protein-based coating films using highly methacrylated casein as a macro-crosslinker. The films exhibited a smooth surface and an even casein distribution as evidenced by both scanning electron and atomic force microscopy, respectively. The mechanical behavior of the casein-based films could be easily tuned by controlling the degree of methacrylation of the bio-based crosslinker. The as-prepared films showed pH-dependent swelling, in which the swelling ability in alkaline medium was stronger than that at acid pH. The mechanical, swelling, rheological and release performance of the casein-based films suggest that these materials have a high potential as enteric coatings for intestinal drug delivery. [ABSTRACT FROM AUTHOR]

Polyphenols comprise a number of natural substances, such as flavonoids, that show interesting biological effects. Among these substances is naringin, a naturally occurring flavanone glycoside found in citrus fruits and Chinese medicinal herbs. Several studies have shown that naringin has numerous biological properties, including cardioprotective, cholesterol-lowering, anti-Alzheimer's, nephroprotective, antiageing, antihyperglycemic, antiosteoporotic and gastroprotective, anti-inflammatory, antioxidant, antiapoptotic, anticancer and antiulcer effects. Despite its multiple benefits, the clinical application of naringin is severely restricted due to its susceptibility to oxidation, poor water solubility, and dissolution rate. In addition, naringin shows instability at acidic pH, is enzymatically metabolized by β-glycosidase in the stomach and is degraded in the bloodstream when administered intravenously. These limitations, however, have been overcome thanks to the development of naringin nanoformulations. This review summarizes recent research carried out on strategies designed to improve naringin's bioactivity for potential therapeutic applications. [ABSTRACT FROM AUTHOR]

[Display omitted] Poor aqueous solubility of preexisting and emerging drug molecules is a common issue faced in the field of pharmaceutics. To address this, particle size reduction techniques, including drug micro- and nanonisation have been widely employed. Nanocrystals (NCs), drug particles with particle sizes below 1 µm, offer high drug content, improved dissolution, and long-acting capabilities. Media milling is the most used method to prepare NCs using of-the-shelf machinery, both at the laboratory and industrial scales. However, early NCs development, especially when limited amounts of the active are available, require the use of milligram-scale media milling. This study introduces a novel mini-scale milling device (Mini-mill) that incorporates temperature control through a water-cooled jacket. The device was used to produce NCs of three model hydrophobic drugs, itraconazole, ivermectin and curcumin, with lowest particle sizes of 162.5 ± 0.4 nm, 178 ± 2 nm, and 116.7 ± 0.7 nm, respectively. Precise control of milling temperature was achieved at 15, 45, and 75°C, with drug dependent particle size reduction trends, with no adverse effects on the milling materials or polymorphic changes in the NCs, as confirmed by calorimetric analysis. Finally, a scale-up feasibility study was carried out in a lab-scale NanoDisp®, confirming that the novel Mini-mills are a material-efficient tool for early formulation development, with potential for scale-up to commercial mills. [ABSTRACT FROM AUTHOR]

[Display omitted] The use of 3D printing for the production of systems intended for oral delivery of diet supplements in the veterinary pharmacy constitutes an attractive technology that has remained unexplored. In this sense, this work studies the design and 3D printing of capsular devices that allow the modified release of urea, which is frequently used as a source of non-protein nitrogen in ruminants, but highly toxic if fast ingested. The devices were printed with combinations of polylactic acid (PLA, water-insoluble) and polyvinyl alcohol (PVA, water-soluble) in order to modulate the urea release through the different parts. The optimization of the designs as well as printing parameters such as extrusion temperature, printing speed, retraction distance and nozzle speed resulted critical to obtain successful capsular devices. In addition, the dissolution studies confirmed that the developed designs showed a controlled release of urea, especially the ones that presented internal partitions. Finally, Logistic and Weibull equations were the kinetic models that best fitted the experimental data corresponding to functions that describe S-shaped dissolution profiles. Overall, this work constitutes a proof of concept and provides the first steps in the development of 3D printed simple devices for the controlled release of supplements and drugs in veterinary pharmacy. [ABSTRACT FROM AUTHOR]

In this research, the potential of soy protein (SPI) based-films as drug delivery devices for ocular therapy was developed. Hence, crosslinked films with a natural and non-cytotoxic crosslinking agent, genipin (Gen), coated with poly(lactic acid) (PLA), were prepared. Filmogenic solutions were loaded with timolol maleate (TM) as a model drug, to be used as drug delivery devices, a novel application for this material. The mechanical properties of the films were studied, observing that with the presence of PLA coating, more rigid materials with improved properties were obtained. Furthermore, the release behavior of TM was evaluated in aqueous medium, it being influenced by the degree of film crosslinking. Furthermore, it was determined that PLA coating decreased TM release rate compared to that of uncoated films. Similarly, this behavior was observed via indirect estimation of the release by assessing the hypotensive effectiveness of the films by in-vivo assays. Through intraocular pressure (IOP) determination tests in rabbits, it was demonstrated that, through the use of high crosslinked and coated films, a significant decrease in IOP could be achieved for prolonged time periods. These results suggest that the use of soy protein-based films as drug delivery systems is highly suitable. [ABSTRACT FROM AUTHOR]

Abstract: The adjuvants approved in human vaccine with recombinant/purified antigens induce weak cellular immune response and so the development of new adjuvant strategies is critical. CpG-ODN has successfully been used as an adjuvant (phase I–III clinical trials) but its bioavailability needs to be improved. We investigated the adjuvant ability of CpG-ODN formulated with a liquid crystal nanostructure of 6-O-ascorbyl palmitate (Coa-ASC16). Mice immunized with OVA/CpG-ODN/Coa-ASC16 elicited a potent specific IgG1, IgG2a, Th1 and Th17 cellular response without systemic adverse effects. These responses were superior to those induced by OVA/CpG-ODN (solution of OVA with CpG-ODN) and to those induced by the formulation OVA/CpG-ODN/Al(OH)3. Immunization with OVA/CpG-ODN/Coa-ASC16 resulted in a long-lasting cell-mediated immune response (at least 6.5 months). Furthermore, Coa-ASC16 alone allows a controlled release of CpG-ODN in vitro and induces local inflammatory response, independent of TLR4 signaling, characterized by an influx of neutrophils and Ly6Chigh monocytes and pro-inflammatory cytokines. Remarkably, the adjuvant capacity of CpG-ODN co-injected with Coa-ASC16 (OVA/CpG-ODN plus Coa-ASC16) was similar to the adjuvant activity of OVA/CpG-ODN, supporting the requirement for whole formulation to help CpG-ODN adjuvanticity. These results show the potential of this formulation, opening a new avenue for the development of better vaccines. [Copyright &y& Elsevier]

Cystic echinococcosis is a zoonotic infection caused by the larval stage of Echinococcus granulosus sensu lato. The disease is characterized by the long-term growth of cysts, most commonly in the liver and lungs. Although an ideal model of cystic echinococcosis should induce the development of cysts in the liver and imitate the natural infection route, the murine model of intraperitoneal is still widely used in the field of experimental theraphy. The aim of the present work was to evaluate the usefulness of the murine model of hepatic CE for preclinical drug trials. The effectiveness of albendazole could also be assessed by measuring the diameter of the hepatic cyst. The albendazole significantly reduced the size of the cysts. The ultrastructural alterations of the germinal layer of hepatic cysts provoked by albendazole coincided with those observed in the intraperitoneal model. Similar results were obtained with both albendazole doses. Therefore, the efficacy of albendazole nanocrystals in the murine model of hepatic cystic echinococcosis was carried out at albendazole doses of 25 mg/kg. The abdominal ultrasound allows us to assess the response of cysts to drugs only in a qualitative manner. Although the size of cysts in the albendazole nanocrystal group was not significantly lower than that observed with albendazole, at the ultrastructural level, a greater extent of damage was observed. The murine model of hepatic cystic echinococcosis can be effectively used for assessing the effect of novel formulations or compounds. The main advantage of this model is that cysts are located in the orthotopic organ, which resembles the location most commonly found in human cases. In future studies, the usefulness of the model for pharmacokinetics studies in hepatic cysts will be evaluated. [ABSTRACT FROM AUTHOR]

The poor aqueous solubility of many approved drugs and most new chemical entities poses a challenge to drug delivery scientists working in academic and industrial labs. Despite the high pharmacological activity these drugs may have, their limited water solubility leads to poor absorption and consequently to sub-therapeutic drug concentrations in target tissues. The formulation of drug nanocrystals (NCs) has emerged as one the most promising approaches for increasing the biopharmaceutical performance of hydrophobic drugs. Initially aimed at increasing the absorption of drugs administered orally, NCs have been increasingly utilised to allow drug delivery via multiple routes, namely, parenteral injections, transdermal, ocular, intranasal, and pulmonary. This review aims to describe the recent progress in the field and demonstrate how the NCs technology enabled the delivery of hydrophobic drugs through multiple administration routes. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Ascorbyl palmitate (Asc16) in polyethyleneglycol 400 (PEG 400)–water mixtures at weight fractions (w/w) between 0.05 and 1.0 were studied by differential scanning calorimetry (DSC) and polarizing microscopy (PM) at different temperatures. The employed PEG 400–water proportions were: 0–25–50% and 75% of polymer. A complete phase diagram was determined for each PEG 400–water mixture. A cubic mesophase and two (probably three) lamellar mesophases were detected in different regions of the phase diagrams. The addition of PEG 400 to the Asc16–water system shifts the limits of the liquid crystalline domains to lower temperature and surfactant concentration. At weight fraction of PEG 400≥50%, the limits of the domain of existence of cubic mesophase shift to low surfactant concentration compared with water-rich systems. The hydrated crystals are Asc16.2·6H2O. If the proportion of water is lower than that value, a mixture of hydrated and anhydrous crystals appears. Heating these crystals produce waxy crystals having melted hydrocarbon bilayers retaining their crystalline structure because the polar bilayers are still rigid. [Copyright &y& Elsevier]

At present, the use of benzimidazole drugs in veterinary medicine is strongly limited by both pharmacokinetics and formulative issues. In this research, the possibility of applying an innovative semi-solid extrusion 3D printing process in a co-axial configuration was speculated, with the aim of producing a new gastro-retentive dosage form loaded with ricobendazole. To obtain the drug delivery system (DDS), the ionotropic gelation of alginate in combination with a divalent cation during the extrusion was exploited. Two feeds were optimized in accordance with the printing requirements and the drug chemical properties: the crosslinking ink, i.e., a water ethanol mixture containing CaCl2 at two different ratios 0.05 M and 0.1 M, hydroxyethyl cellulose 2% w/v, Tween 85 0.1% v/v and Ricobendazole 5% w/v; and alginate ink, i.e., a sodium alginate solution at 6% w/v. The characterization of the dried DDS obtained from the extrusion of gels containing different amounts of calcium chloride showed a limited effect on the ink extrudability of the crosslinking agent, which on the contrary strongly influenced the final properties of the DDS, with a difference in the polymeric matrix toughness and resulting effects on floating time and drug release. [ABSTRACT FROM AUTHOR]

Self-dispersible nanocrystals of azoxystrobin and cyproconazole were obtained by combining wet bead milling and spray-drying. Nanocrystals formulations were characterized and evaluated by their antifungal activity against S. minor and S. rolfsii. The mean particle sizes of azoxystrobin and cyproconazole nanosuspensions were 172.78 and 277.37 nm. Milling rotational frequency and milling time were the most significant process parameters. The contents of azoxystrobin and cyproconazole in their solid formulations were 45.3 and 43.3% w /w. Spray-drying increased the particle size of fungicide nanocrystals (azoxystrobin, 323.68 nm; cyproconazole, 456.53 nm). The method of production showed a solid yield of 44.5% for azoxystrobin and 34.5% for cyproconazole. The methodology used in this study does not affect the crystallinity of fungicides. Nanocrystal formulations remarkably improved the performance of fungicides and have no negative consequences on peanut growth. The use of self-dispersible nanocrystals is presented as a potential technology to increase the efficacy of fungicides. Unlabelled Image • Self-dispersible nanocrystals of azoxystrobin and cyproconazole were prepared by wet bead milling followed by spray-drying. • The milling rotational frequency and time had significant roles in determining the particle size distribution. • Fungicide nanocrystals presented particle sizes below 300 nm. • Preparation of nanocrystals by wet bead milling did not affect crystallinity of fungicides. • Nanocrystal formulations remarkably improved performance of fungicides against S. minor and S. rolfsii. [ABSTRACT FROM AUTHOR]

Abstract Cystic echinococcosis (CE), which is caused during the metacestode larval stage of Echinococcus granulosus , is a life-threatening disease and is very difficult to treat. At present, the FDA-approved antihelmintic drugs are mebendazole (MBZ), albendazole (ABZ) and its principal metabolite ABZ sulfoxide (ABZSO), but as these have a therapeutic efficacy over 50%, underlining the need for new drug delivery systems. The aim of this work was the optimization and characterization of previously developed ABZ lipid nanocapsules (ABZ-LNCs) and evaluate their efficacy in mice infected with E. granulosus. LNCs were prepared by the phase inversion technique and characterized in terms of size, surface charge, drug loading, and in vitro stability followed by an in vivo proof-of-concept using a murine model infected with E. granulosus. Stable particle dispersions with a narrow size distribution and high efficiency of encapsulation (≥90%) were obtained. ABZ-LNCs showed a greater chemoprophylactic efficacy than ABZ suspension administered by the oral route as 4 out of the 10 ABZ-LNCs treated mice did not develop any cysts, whereas the infection progressed in all mice from the ABZ suspension group. Regarding the ultrastructural studies of cysts, mice treated with ABZ-LNCs or ABZ suspension revealed changes in the germinal layer. However, the extent of the damage appeared to be greater after ABZ-LNC administration compared to the suspension treatment. These results suggest that ABZ-LNCs could be a promising novel candidate for ABZ delivery to treat CE. Graphical abstract Image 1 Highlights • Optimised ABZ-LNCs were obtained through the phase inversion method. • ABZ-LNCs with a EE >90% were stable for at least 2 months. • ABZ remained encapsulated in LNCs after its incubation in simulated biological fluids. • ABZ-LNCs showed a greater chemoprophylactic efficacy than ABZ suspension. • ABZ-LNCs could be a promising strategy for cystic echinococcosis treatment. [ABSTRACT FROM AUTHOR]

Human alveolar echinococcosis is caused by the fox tapeworm Echinococcus multilocularis and is usually fatal if left untreated. Medical treatment with albendazole (ABZ) remains an effective option. However, due to its low aqueous solubility, ABZ is poorly and erratically absorbed following oral administration resulting in low drug levels in plasma and liver distribution. Thus, there arises the need to find a simple, efficient and scalable method to produce new ABZ formulations with increased bioavailability. Bearing this in mind, ABZ nanocrystals (ABZ-NCs) appears to be a useful tool to achieve this goal. The aim of the current study was to investigate the chemoprophylactic and clinical efficacy of an ABZ-NC formulation on mice infected with E. multilocularis . In the chemoprophylactic efficacy study, mean weight of the cysts recovered from the ABZ-NC group was 50% lower than that recorded from untreated mice, whereas the treatment with ABZ suspension did not show preventive effect. The viability of protoscoleces isolated from ABZ-NC treated mice was significantly lower than control groups. In the clinical efficacy studies, both ABZ formulations resulted in a reduction in the mean weight of the cysts obtained from mice, however only the treatment with the nanosuspension revealed significant differences ( P < 0.05) compared to the control groups. Treatment with ABZ-NCs reduced the weight of the cysts by 77% and the viability of their protoscoleces to 34%. All these results coincided with the tissue damage determined at the ultrastructural level. The enhanced chemoprophylactic and clinical efficacy of ABZ-NCs observed in this study could be attributed to an increase in the oral bioavailability of the drug. In a next step, we will characterize the cyst concentration profile after the administration of ABZ-NCs in mice infected with E. multilocularis . [ABSTRACT FROM AUTHOR]

Glaucoma is characterized by increased intraocular pressure (IOP) that results in blindness if it remains untreated. Acetazolamide (AZM) is a carbonic anhydrase inhibitor, mainly used to reduce IOP in the treatment of glaucoma. However, the potential of topical treatment is limited, due to its low permeability across the ocular epithelium. An alternative to overcome this limitation is the incorporation of AZM in nanoparticulate systems, such as polymeric nanocapsules (NCs). In this way, the aim of this work was to prepare and characterize NC formulations containing AZM, using ethylcellulose (EC) and Eudragit ® RS100 (EUD) as encapsulating polymers. The formulations showed high encapsulation efficiency. Particle size measurements showed that NCs are in the nanometric range. Comparing both groups of formulations, the NCEC proved to be smaller than those prepared with EUD. The formulations prepared with EC showed negative zeta potentials, while NCs of EUD were positively charged. For both groups of formulations, no more than 30% of drug was released in 120 min. Ex vivo and in vivo studies evidenced that the NCEC formulations were the most efficient, because an increased amount of permeated drug was observed, along with a greater IOP decrease and longer duration of the effect in normotensive rabbits. [ABSTRACT FROM AUTHOR]

Therapeutic failures attributed to medical management of cystic echinococcosis (CE) with albendazole (ABZ) have been primarily linked to the poor drug absorption rate resulting in low drug level in plasma and hydatid cysts. Lipid nanocapsules (LNCs) represent nanocarriers designed to encapsulate lipophilic drugs, such as ABZ. The goals of the current work were: (i) to characterize the plasma and cyst drug exposure after the administration of ABZ as ABZ-LNCs or ABZ suspension (ABZ-SUSP) in mice infected with Echinococcus granulosus , and ii) to compare the clinical efficacies of both ABZ formulations. Enhanced ABZ sulphoxide (ABZ-SO) concentration profiles were obtained in plasma and cysts from ABZ-LNC treated animals. ABZSO exposure (AUC 0–LOQ ) was significantly higher in plasma and cyst after the ABZ-LNC treatments, both orally and subcutaneously, compared to that observed after oral administration of ABZ-SUSP. Additionally, ABZSO concentrations measured in cysts from ABZ-LNC treated mice were 1.7-fold higher than those detected in plasma. This enhanced drug availability correlated with an increased efficacy against secondary CE in mice observed for the ABZ-LNCs, while ABZ-SUSP did not reach differences with the untreated control group. This new pharmacotechnically-based strategy could be a potential alternative to improve the treatment of human CE. [ABSTRACT FROM AUTHOR]

Modern subunit vaccines require the development of new adjuvant strategies. Recently, we showed that CpG-ODN formulated with a liquid crystal nanostructure formed by self-assembly of 6-O-ascorbyl palmitate (Coa-ASC16) is an attractive system for promoting an antigen-specific immune response to weak antigens. Here, we showed that after subcutaneous injection of mice with near-infrared fluorescent dye-labeled OVA antigen formulated with Coa-ASC16, the dye-OVA was retained at the injection site for a longer period than when soluble dye-OVA was administered. Coa-ASC16 alone elicited a local inflammation, but how this material triggers this response has not been described yet. Although it is known that some materials used as a platform are not immunologically inert, very few studies have directly focused on this topic. In this study, we explored the underlying mechanisms concerning the interaction between Coa-ASC16 and the immune system and we found that the whole inflammatory response elicited by Coa-ASC16 (leukocyte recruitment and IL-1β, IL-6 and IL-12 production) was dependent on the MyD88 protein. TLR2, TLR4, TLR7 and NLRP3-inflammasome signaling were not required for induction of this inflammatory response. Coa-ASC16 induced local release of self-DNA, and in TLR9-deficient mice IL-6 production was absent. In addition, Coa-ASC16 revealed an intrinsic adjuvant activity which was affected by MyD88 and IL-6 absence. Taken together these results indicate that Coa-ASC16 used as a vaccine platform is effective due to the combination of the controlled release of antigen and its intrinsic pro-inflammatory activity. Understanding how Coa-ASC16 works might have significant implications for rational vaccine design. [ABSTRACT FROM AUTHOR]

Abstract: Cystic echinococcosis is a chronic, complex, and still neglected disease. Although albendazole has demonstrated efficacy, only about one-third of patients experience complete remission or cure and 30–50% of treated patients develop some evidence of a therapeutic response. Different strategies have been developed in order to improve the albendazole water solubility and dissolution rate. The aim of the current work was to investigate the chemoprophylactic and clinical efficacy of an albendazole:poloxamer 188 solid dispersion formulation on mice infected with Echinococcus granulosus metacestodes. Albendazole formulated as solid dispersion had greater chemoprophylactic and clinical efficacy than albendazole alone. The improved in therapeutic efficacy could be a consequence of the increase in the systemic availability of albendazole sulfoxide. The work reported here demonstrates that in vivo treatment with albendazole:poloxamer 188 impairs the development of the hydatid cysts. This new pharmacotechnically based strategy could be a suitable alternative for treating cystic echinococcosis in humans. [Copyright &y& Elsevier]

Highlights: [•] Acetazolamide complexes exhibited a solid-state dependent oral absorption. [•] Complexes of ACZ showed a pronounced improvement of the dissolution profile of ACZ. [•] Complexes of ACZ enhancement of the IOP-lowering effect of ACZ. [ABSTRACT FROM AUTHOR]

The main objectives of this study were (a) to evaluate the in vitro performance of the rapid disintegration tablets as a way to improve the solid dispersions and (b) to study the in vivo pharmacokinetics of the albendazole modified formulation in dogs. Rapid disintegration of tablets seems to be a key factor for efficiency of solid dispersions with regard to improvement of the albendazole bioavailability. The in vivo assays performed on dogs showed a marked increase in drug plasma exposure when albendazole was given in solid dispersions incorporated into rapid disintegration tablets compared with conventional solid dosage form. [ABSTRACT FROM AUTHOR]

Solid dispersions (SDx) containing Indomethacin (IND), a poorly water-soluble drug, and the disintegrant excipient sodium croscarmellose (SC) were prepared by a co-drying method and characterized by Infrared spectroscopy (FT-IR), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). An FT-IR analysis performed on IND-SC solid dispersion and their physical mixtures indicated that IND does not interact with SC in the solid state. An analysis of the information produced by DSC, XRD, and SEM confirmed that the crystalline α-form of IND was homogeneously incorporated into SDx. IND release from SDx was significantly greater than that from its corresponding physical mixtures with the high homogeneous molecular dispersion and the crystalline modification of IND appearing to be the cause. This behavior may have a beneficial effect on the biopharmaceutical performance of this drug. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the performance of 6-O-Lauryl- l-ascorbic acid nanostructures (coagels) as vehicles for acetazolamide (AZM) in ophthalmic administration by in vitro and in vivo experimental tests. Methods: The systems of coagel + AZM were evaluated in terms of their in vitro release (dialysis membrane), permeability (isolated cornea), pharmacological effectiveness [intraocular pressure (IOP)-reduction in normotensive rabbits], and potential irritant effects. Results: The results concerning AZM permeation were better when vehiculized in coagels compared with ringer solution, which was evident from the AZM steady-state flux and Papp values ( J=1.43 μg/min and Papp=3.04 cm.s1). As a consequence of this increase in permeation, the coagel-AZMs were more effective in lowering the IOP, according to the results obtained from the in vivo assays. Coagels loaded with 0.4% (W/W) of AZM showed a higher hypotensive effect in rabbits compared with the commercial formulation AZOPT® (brinzolamide 1%), mainly due to the prolonged effect of the former. In all cases, the intensity of irritation was time dependent. The sodium lauryl sulphate solution (2%) used as a positive control produced serious injury 30 min postadministration. This effect caused irritation, which decreased slowly and even at 180 min, the discomfort was still considerable. However, in the case of coagels, a mild-to-moderate effect was observed. Conclusions: The incorporation of AZM in coagels seems to improve the ocular bioavailability of this drug. Coagel-AZM 0.4% showed a higher hypotensive effect, with a mild-to-moderate irritant effect. These systems could be administrated in human beings, although more detailed studies still need to be carried out. [ABSTRACT FROM AUTHOR]

Abstract: This work addresses the ascorbyl palmitate (Asc16) aqueous systems. It has been studied through differential scanning calorimetry (DSC) and polarizing microscopy (PM) at different temperatures over a wide range of concentrations (weight fractions (w/w) between 0.05 and 1.0), allowing the determination of a complete phase diagram. When possible, the findings were corroborated with literature data. Systems below C ≈0.48wt fraction show hydrated crystals in an isotropic liquid, which lead to a lamellar liquid crystal when heated to about 60°C. Above this concentration, the phase transition occurs at about 80°C, giving a cubic liquid crystal which in turn becomes lamellar liquid crystal at about 90°C. The texture of this lamellar mesophase is different to that produced at lower concentrations. It has been determined, through DSC analysis of the melting peaks of water, computer simulation of the hydration of Asc16 molecules and a model of the hydrated aggregates (hydrated crystals and lamellar mesophase), that low concentration liquid crystals exist provided bulk water is present in the system. Two other kinds of water but bulk were detected: a first hydration shell, with water molecules strongly attached by hydrogen bonds to the oxygen and hydrogen atoms of the polar headgroup, which does not melt and is then undetectable by DSC (11.47±0.95 water molecules per surfactant molecule) and a second hydration layer containing 59±17 water molecules per surfactant one (apart from those in the first hydration layer). The number of water molecules in the second hydration layer decreases as the surfactant concentration increases, and vanishes at C =0.62±0.01wt fraction (computer simulation and structure model data) or at C =0.667±0.007 (DSC). At very high concentrations the formation of mesophases is preceded by the melting of the chains, giving a waxy texture when viewed at the polarizing microscope, maintaining the structure of crystals because the anhydrous polar bilayer remains “solid”. [Copyright &y& Elsevier]

Abstract: Amiodarone aqueous systems at concentrations C ⩽3mg/mL were studied with different techniques (conductivity, solubility, ion-selective electrodes, pH, viscosity, polarizing microscopy, computational simulation, electron microscopy and fluorescence at various temperatures. The Krafft point (TK =70.6°C) was determined. A partial phase diagram was plotted showing the critical micelle concentration (CMC) dependence on temperature, the solubility and a transition between a coacervate and an unstable gel below TK as a function of temperature. The nature of aggregates below TK at different concentrations was determined. Micellization is an entropy-driven process which is probably caused by a strong dehydration of the amiodarone backbone on micellization. CMC, micelle aggregation number and TK given in earlier literature were misinterpreted in the original articles and are re-interpreted in this work. [Copyright &y& Elsevier]

Topical administration to the eye for the treatment of glaucoma is a convenient route because it increases the patient comfort. Timolol can efficiently diminish the intraocular pressure (IOP) of the eye; however the topical application as a solution of timolol maleate (TM) has poor therapeutic index and presents severe side effects. The encapsulation of timolol in nanomaterials has appeared as a technology to increase its residence time in the eye thus achieving a sustained release and consequently diminishing the doses of this drug and their number. The preparation of nanogels (NGs) based on N-isopropylacrylamide (NIPA) and acrylic acid (AAc), easily synthesized by precipitation/dispersion free radical polymerization, is reported in this paper. Such NGs presented excellent dispersability in eye simulated fluid and ideal size for topical application. NGs can load efficiently timolol through ionic interaction, and the in vitro release showed that NGs deliver timolol in a sustained manner. In vivo sustained efficacy of the NGs-timolol nanoformulations was demonstrated in rabbit's glaucoma model, in which the IOP could be diminished and maintained constant for 48 h with only one application. Overall, the synthesized NGs in combination with timolol have potential as drug delivery system for glaucoma therapy. Unlabelled Image • Poly(NIPA- co -AAc) nanogels were prepared through a simple methodology. • Nanogels were loaded with timolol through strong ionic interaction. • In vitro release showed a slow and sustainable release of timolol. • In vivo studies demonstrated an improve in therapeutic index of timolol for glaucoma. [ABSTRACT FROM AUTHOR]

• 3D printing is a useful process for designing innovative oral solid dosage forms. • MESO-PP allows printing at low temperatures and without the use of solvents. • A floating printlet of ricobendazole is obtained and characterized. • The use of Gelucire 50/13 as ink allows to control the release of the drug. This paper describes a melting solidification printing process (MESO-PP) capable of obtaining printed oral solid dosage forms in a safe, versatile, and robust manner avoiding the use of solvents and high temperatures. MESO-PP and Gelucire® 50/13 (fatty polyethylene glycol esters) as ink can be used to obtain a floating sustained-release system with the aim of improving the dissolution and absorption of drugs, such as ricobendazole (RBZ), which have a low and erratic bioavailability. Gelucire 50/13 can be considered a good material to formulate inks using MESO-PP. As a model, the RBZ allowed us to assess that there were no changes in crystallinity and the API-ink interactions were ruled out using TGA, DSC, XRD and FT-IR assays. A batch of printlets, obtained using MESO-PP, fulfilled USP requirements regarding uniformity of mass (827 ± 9 mg) and drug content (211 ± 5 mg). Hardness and friability were 39.23 ± 9.65 N and 1.07 ± 0.5% respectively, just above the 1% USP tablet-friability limit. It was possible to obtain tablets of different sizes with high precision (r2 = 0.995). In vitro dissolution test showed that the printlet had a sustained-release of RBZ (only 7% after 15 min), that erosion was the predominant mechanism for drug release (n-value of Korsmeyer-Peppas equation = 0.991; r2 = 0.99) and that changes in the internal structures modify the release. Consequently, MESO-PP can be considered an excellent alternative to obtain solid pharmaceutical dosage forms with variable geometries for different pharmaceutical applications. [ABSTRACT FROM AUTHOR]

• RBZ-NCs were obtained by media milling and spray drying with high process yield. • A fast NCs redispersion was observed in the in vitro characterization. • No physicochemical changes were observed in RBZ after the fabrication process. • RBZ-NCs presented an improved biopharmaceutical performance. • RBZ-NCs showed a significantly increased plasma exposure after oral administration. Helminthic infections are produced by different types of worms and affect millions of people worldwide. Benzimidazole compounds such as ricobendazole (RBZ) are widely used to treat helminthiasis. However, their low aqueous solubility leads to poor gastrointestinal dissolution, absorption and potential lack of efficacy. The formulation of nanocrystals (NCs) have become the strategy of preference for hydrophobic drugs. In this work, we prepared RBZ NCs (RBZ-NCs) by an optimized combination of bead milling and spray-drying. Following the physicochemical characterization, a comparative pharmacokinetic evaluation of RBZ-NCs was performed in dogs using as controls a micronized powdered form of RBZ (mRBZ) and a physical mixture of drug and stabilizer 1:1 (PM). The particle size of the redispersed RBZ-NCs was 181.30 ± 5.93 nm, whereas DSC, PXRD and FTIR analyses demonstrated that the active ingredient RBZ remained physicochemically unchanged after the manufacture process. RBZ-NCs exhibited improved in vitro biopharmaceutical behaviour when compared to mRBZ. Consequently, the pharmacokinetic trial demonstrated a significant increase in the drug oral absorption, with an AUC 0-∞ 1.9-fold higher in comparison to that obtained in animals treated with mRBZ. This novel formulation holds substantial potential for the development of new/alternative treatments for helminth infections both in human and veterinary medicine. [ABSTRACT FROM AUTHOR]

• Anti-echinococcal activity of menthol pentanol, a novel prodrug, was demonstrated. • Menthol pentanol improved the efficacy of menthol on Echinococcus multilocularis. • The in vivo efficacy of menthol pentanol was similar to the efficacy of albendazole. Alveolar echinococcosis is one of the most dangerous parasitic zoonoses. This disease, widely distributed in the northern hemisphere, is caused by the metacestode stage of the tapeworm Echinococcus multilocularis. All surgical and non-surgical patients should perform chemotherapy with benzimidazoles, mainly with albendazole. However, the efficacy of albendazole is variable due to its deficient pharmacokinetic properties. Therefore, the need to find new therapeutic alternatives for the treatment of alveolar echinococcosis is evident. Menthol is a natural compound of low toxicity, used in industries such as cosmetics and gastronomy and generally recognized as safe by the Food and Drug Administration. In addition, menthol has important pharmacological effects and is effective against a wide variety of organisms. The development of prodrugs allows improving the pharmacokinetic properties of the parental drug. To improve lipophilicity and therefore the bioavailability of menthol, a novel prodrug called menthol-pentanol was developed by masking the functional polar group of menthol by linking n-pentanol by a carbonate bond. The aim of the current work was to evaluate the in vitro and in vivo efficacy of menthol and menthol-pentanol against E. multilocularis. Menthol-pentanol had a greater protoscolicidal effect than menthol. In addition, the prodrug demonstrated a similar clinical efficacy to albendazole. The increase in lipophilicity of the prodrug with respect to menthol was reflected in an increase in its antiparasitic activity against E. multilocularis. Thus, menthol-pentanol appears as a promising candidate for further evaluation as a potential alternative for the treatment of alveolar echinococcosis. Summary: Menthol pentanol, a new prodrug of menthol with greater lipophilicity, demonstrated greater anti-echinococcal activity than menthol and similar to albendazole against Echinococcus multilocularis. Image, graphical abstract [ABSTRACT FROM AUTHOR]

The main objectives of this study were (a) to evaluate the in vitro performance of the rapid disintegration tablets as a way to improve the solid dispersions and (b) to study the in vivo pharmacokinetics of the albendazole modified formulation in dogs. Rapid disintegration of tablets seems to be a key factor for efficiency of solid dispersions with regard to improvement of the albendazole bioavailability. The in vivo assays performed on dogs showed a marked increase in drug plasma exposure when albendazole was given in solid dispersions incorporated into rapid disintegration tablets compared with conventional solid dosage form. [ABSTRACT FROM AUTHOR]