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Increasing the solubility of drugs is a recurrent objective of pharmaceutical research, and one of the most widespread strategies today is the formulation of nanocrystals (NCs). Beyond the many advantages of formulating NCs, their incorporation into solid dosage forms remains a challenge that limits their use. In this work, we set out to load Atorvastatin NCs (ATV-NCs) in a delivery device by combining 3D scaffolds with an "in situ" loading method such as freeze-drying. When comparing two infill patterns for the scaffolds at two different percentages, the one with the highest NCs load was chosen (Gyroid 20 % infill pattern, 13.8 ± 0.5 mg). Colloidal stability studies of NCs suggest instability in acidic media, and therefore, the system is postulated for use as a sublingual device, potentially bypassing stomach and hepatic first-pass effects. An ad hoc dissolution device was developed to mimic the release of actives. The nanometric size and properties acquired in the process were maintained, mainly in the dissolution rate and speed, achieving 100 % dissolution of the content in 180 s. Based on these results, the proof of concept represents an innovative approach to converting NCs suspensions into solid dosage forms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A study was performed for the development and validation of a method of High Performance Liquid Chromatography (HPLC) for the identification and simultaneous quantification of Gallein and Human Serum Albumin (HSA). In addition, this work presents the development and physicochemical characterization of this new pharmaceutical formulation of HSA nanoparticles loaded with Gallein for potential use in the treatment of Alzheimer's disease. The method was developed with the purpose of determining the performance of the synthesis process of nanoparticles and the efficiency of encapsulation of the drug in the nanosystem. The HPLC mobile phase consisted of ACN:H 2 O:TEA:H 3 PO 4 (50:49.8:0.1:0.1 v/v/v) pumped at a flow rate of 0.8 mL/min, isocratic mode, and the measurement were carried out at 220 nm. Chromatographic runs were performed on a C18 column (150 × 4.60 mm; 5 μm size particles). The HPLC-method was validated following the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines and was used to simultaneously quantify the two components of the nanoformulation. Thus, the values obtained through the validated method were 43 % for drug encapsulation efficiency (% EE) and the synthesis performance (% yield) was 96 %. Moreover, the nanoformulation was characterized by DLS, the results showed that the average particle size was 217 nm, with a PDI of (0.085 ± 0.005) and a potential Z of -29.7 mV. Therefore, the developed method has proven useful in providing accurate simultaneous measurements of HSA and Gallein from albumin nanoparticles. It is advantageous since it is able to reduce the time and facilitate the determination of Gallein encapsulation efficiency and yield of albumin nanoparticles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

New adjuvant strategies are needed to improve protein-based subunit vaccine immunogenicity. We examined the potential to use nanostructure of 6-O-ascorbyl palmitate to formulate ovalbumin (OVA) protein and an oligodeoxynucleotide (CpG-ODN) (OCC). In mice immunized with a single dose, OCC elicited an OVA-specific immune response superior to OVA/CpG-ODN solution (OC). Rheological studies demonstrated OCC's self-assembling viscoelastic properties. Biodistribution studies indicated that OCC prolonged OVA and CpG-ODN retention at injection site and lymph nodes, reducing systemic spread. Flow-cytometry assays demonstrated that OCC promoted OVA and CpG-ODN co-uptake by Ly6C hi CD11b hi CD11c+ monocytes. OCC and OC induced early IFN-γ in lymph nodes, but OCC led to higher concentration. Conversely, mice immunized with OC showed higher serum IFN-γ concentration compared to those immunized with OCC. In mice immunized with OCC, NK1.1+ cells were the IFN-γ major producers, and IFN-γ was essential for OVA-specific IgG2c switching. These findings illustrate how this nanostructure improves vaccine's response., Competing Interests: Declaration of competing interest All authors declared that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Atorvastatin (ATV) is a first-line drug for the treatment of hyperlipidemia. This drug presents biopharmaceutical problems, partly due to its low solubility and dissolution rate. In this work, nanocrystals of ATV stabilized with Tween 80® were designed by wet milling. A full factorial design was applied to optimize the process. Additionally, a cryoprotectant agent (maltodextrin, MTX) was identified, which allowed maintaining the properties of the nanocrystals after lyophilization. The storage stability of the nanocrystals was demonstrated for six months in different conditions. The obtained nanocrystal powder was characterized using SEM, EDXS, TEM, DSC, TGA, FT-IR, and XRD, showing the presence of irregular crystals with semi-amorphous characteristics, likely due to the particle collision process. Based on the reduction in particle size and the decrease in drug crystallinity, a significant increase in water and phosphate buffer (pH 6.8) solubility by 4 and 6 times, respectively, was observed. On the other hand, a noticeable increase in the dissolution rate was observed, with 90 % of the drug dissolved within 60 min of study, compared to 30 % of the drug dissolved within 12 h in the case of the untreated drug or the physical mixture of components. Based on these results, it can be concluded that the nano-milling of Atorvastatin stabilized with Tween 80® is a promising strategy for developing new formulations with improved biopharmaceutical properties of this widely used drug., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: In this work, in order to establish a better comprehension of the association between Argentina and its neighbor countries' capacity, and COVID-19 burden during the first 3 months, different indicators were evaluated., Method: We analyzed the association between GHSI, INFORM index and COVID-19 burden (number of confirmed cases and deaths), also the number of tests, lethality and the stringency of Governmental policies were evaluated., Results: Uruguay, Paraguay, and Bolivia started earlier different prevention measures. The number of tests differs, as Chile is the 1 that makes more. Uruguay and Paraguay register fewer positive cases and deaths from COVID-19. The GHS index is led by Brazil, followed by Argentina, and then Chile. However, the INFORM index is led by Uruguay followed by Argentina, while Chile and Paraguay are on par., Conclusion: The countries that took preventive measures earlier and carried out a more tests are the ones that are obtaining the best results against COVID-19.

Neglected tropical diseases are a major health problem throughout the world, and there are few effective and safe drugs. In this study, we report the design and synthesis of a novel series of carbonates of eugenol using different aliphatic alcohols and N,N-carbonyldiimidazole. Spectroscopic techniques, including 1 H nuclear magnetic resonance (NMR), 13 C NMR, Fourier transform infrared, and high-resolution mass spectrometry, were used to confirm the structures of the synthesized compounds. In vitro and in silico studies of prodrugs of eugenol were performed to determine their antiplasmodial, trypanocidal, and leishmanicidal activities, and also their cytotoxicity. Compounds were highly active against Leishmania braziliensis and Plasmodium falciparum, whereas the activity shown for Trypanosoma cruzi was moderate. Molecular docking was used to determine a possible mode of action of eugenol against the dihydroorotate dehydrogenase of the three parasites (TcDHODH, LbDHODH, and PfDHODH). Notably, the docking results showed that eugenol not only has binding energy similar to that of the natural substrate (-7.2 and -7.1, respectively) but also has interactions with relevant biological residues of PfDHODH. This result indicates that eugenol could act as a substrate for PfDHODH in the pyrimidine biosynthesis pathway of P. falciparum. In conclusion, the combination of certain aliphatic alcohols and eugenol through a carbonate bond could significantly increase the antiparasitic activity of this class of compounds, which merits further studies., (© 2021 Deutsche Pharmazeutische Gesellschaft.)

Glaucoma is a degenerative optic neuropathy characterized by increased intraocular pressure that if untreated can result in blindness. Ophthalmological drug therapy is a challenge of great clinical importance due to the diversity of ocular biological barriers which commonly causes limited or no effectiveness for drugs delivered through the eye. In this work, we proposed the development of nanosized cubic liquid crystals (cubosomes) as a new drug carrier system for latanoprost, an anti-glaucoma drug. Latanoprost-loaded phytantriol cubosomes (CubLnp) were prepared using a top-down method. Latanoprost concentration in the formulations ranged from 0.00125% to 0.02% w/v. All cubosomes displayed an average size around 200 nm, a low polydispersity index of 0.1 and zeta potential values around -25 mV, with an encapsulation efficiency of about 90%. Structural studies revealed that cubosomes displayed a double-diamond surface, Pn3m cubic-phase structure, and was not affected by drug loading. Calorimetric studies revealed a fast and exothermic interaction between latanoprost and cubosomes. According to in vitro essays, latanoprost release from cubosomes was slow in time, evidencing a sustained release profile. Based on this behavior, the in vivo hypotensive intraocular effect was evaluated by means of the subconjunctival administration of CubLnp in normotensive rabbits. We obtained promising results in comparison with a marketed latanoprost formulation (0.005% w/v)., (Copyright © 2021 Elsevier B.V. All rights reserved.)

We are reporting for the first time the synthesis and application of an innovative nanometric system for the controlled topic release of melatonin in the retina. The ethylcellulose nanocapsules were characterized by diverse physicochemical techniques (scanning electron microscopy, zeta potential, hydrodynamic diameters) and an in vitro release study was done. A complete ex vivo and in vivo trans-corneal permeation and an irritation study were carried out with the new formulations in albino rabbits, to which a retinal degenerative model was induced. The results obtained demonstrate that the in vitro release of melatonin (1 mg/mL and 2 mg/mL) transported by nanocapsules is slower when compared to a solution of melatonin. Greater penetration of melatonin through the cornea was demonstrated by ex vivo and in vivo tests. This can be attributable to an enhanced neuroprotective effect of melatonin on retinal ganglion cells when it is included in ethylcellulose nanocapsules compared to a solution of melatonin. These outstanding findings add promising new perspectives to current knowledge about administrations using nano-technological tools in the treatment of neurodegenerative diseases at the ocular level., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Fasciola hepatica is helminth parasite found around the world that causes fasciolosis, a chronic disease affecting mainly cattle, sheep, and occasionally humans. Triclabendazole is the drug of choice to treat this parasite. However, the continuous use of this drug has led to the development of parasite resistance and, consequently, the limitation of its effectiveness. Hence, vaccination appears as an attractive option to develop. In this work, we evaluated the potential of F. hepatica Kunitz-type molecule (FhKTM) as an antigen formulated with a liquid crystal nanostructure formed by self-assembly of 6-O-ascorbyl palmitate ester (Coa-ASC16) and the synthetic oligodeoxynucleotide containing unmethylated cytosine-guanine motifs (CpG-ODN) during an experimental model of fasciolosis in mice, and we further dissected the immune response associated with host protection. Our results showed that immunization of mice with FhKTM/CpG-ODN/Coa-ASC16 induces protection against F. hepatica challenge by preventing liver damage and improving survival after F. hepatica infection. FhKTM/CpG-ODN/Coa-ASC16-immunized mice elicited potent IFN-γ and IL-17A with high levels of antigen-specific IgG1, IgG2a, and IgA serum antibodies. Strikingly, IL-17A blockade during infection decreased IgG2a and IgA antibody levels as well as IFN-γ production, leading to an increase in mortality of vaccinated mice. The present study highlights the potential of a new vaccine formulation to improve control and help the eradication of F. hepatica infection, with potential applications for natural hosts such as cattle and sheep., (Copyright © 2020 Silvane, Celias, Romagnoli, Maletto, Sanchez Vallecillo, Chiapello, Palma, Allemandi, Sanabria, Pruzzo, Motrán and Cervi.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The aim of this work was evaluate the antioxidant effect of ascorbyl laurate (ASC12) based nanostructures applied topically to the cornea of ocular normotensive and hypertensive rabbits. The ASC12 was chosen for its capacity to form liquid lyotropic crystal and keeps its free radical trapping power., Methods: The hypertension model was performed in six rabbits and was obtained by the application of intracameral injections of alpha-chymotrypsin in the right eye. A single 50 ml dose of ascorbyl laurate coagel 2% w/v (COA-ASC12) was applied topically to the cornea of six normotensive and six hypertensive rabbits. The aqueous humor samples were obtained before and after instillation of COA-ASC12 at different times (2 h and 4 h). Antioxidant capacity was determined via the reduction reaction with iron and tripyridyltriazine (FRAP) and the total proteins were measured using the Bradford reagent., Results: The kinetic antioxidant capacity in the aqueous humor of normotensive and hypertensive rabbits showed a maxim increment at 4 h instillation. Also, the antioxidant capacity in the aqueous humor of hypertensive rabbits was ten times lower than in normotensive rabbits., Conclusion: This type of nanostructures has the potential to significantly improve the topical formulation for the prophylaxis and treatment of several eye diseases., (Copyright © 2019. Published by Elsevier B.V.)

This study aims to assess the enhancement of the chemical and sensory properties of roasted peanuts during storage, through the application of high-protein defatted peanut flour (DPF) coatings incorporated with and without antioxidants. The control sample without coating, packed in normal atmosphere (control), showed the highest conjugated dienes (CD) increment (from 1.17 on day 0 to 3.60 on day 180). Roasted peanuts without coating, packed in high barrier bags under vacuum, reached the lowest CD at day 180 (1.92). Conjugated trienes and peroxide values were analogous to CD. The control exhibited the greatest decrease in α-tocopherol (from 27.65 mg/100 g on day 0 to 21.32 mg/100 g on day 180) and γ-tocopherol (from 21.91 mg/100 g on day 0 to 14.99 mg/100 g on day 180). 3-Methylpyridine and 2,5-dimethylpyrazine decreased with storage time only for the control, which had the highest increase in oxidized flavor (from 0 on day 0 to 13.30 on day 180), cardboard (from 7.67 on day 0 to 15.23 on day 180), and astringency. The lowest decreases in roasted peanutty scores were seen in coated samples. DPF coatings delayed roasted peanuts oxidation, enhancing their sensory properties and shelf life compared with the control sample. PRACTICAL APPLICATION: Defatted peanut flour (DPF) is a byproduct obtained during peanut oil extraction and is a possible material for edible film preparation. This strategy adds value to the peanut industry by transforming a by-product into a material with the potential to develop biodegradable and economical films. The application of this DPF-based edible coating on the surface of roasted peanuts may have contributed to extent product's shelf life, allowing for coated products to be packaged in lower barrier and less expensive materials. Use of peanut material to coat peanuts avoids the risk of allergen protein cross contamination, which would be highly valuable for the food industry., (© 2019 Institute of Food Technologists®.)

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., (Copyright © 2019. Published by Elsevier Inc.)

Oxidative stress triggers ocular neurodegenerative diseases, such as glaucoma or macular degeneration. The increase of reactive oxygen and nitrogen species in retinal ganglion cells (RGCs) causes damage to the structure and function of the axons that make up the optic nerve, leading to cell death arising from apoptosis, necrosis or autophagy in the RCGs. The use of antioxidants to prevent visual neurodegenerative pathologies is a novel and possibly valuable therapeutic strategy. To investigate in vitro and in vivo neuroprotective efficacy of melatonin (MEL) in RGCs, we used a model of oxidative glutamate (GLUT) toxicity in combination with l-butionin-S, R-sulfoximine (BSO), which induces cell death by apoptosis through cytotoxicity and oxidative stress mechanisms. Histological sectioning and immunohistochemical assays using the TUNEL technique were performed to determine the damage generated in affected cells and to observe the death process of RGCs. Whit BSO-GLUT the results revealed a progressive RGCs death without any significant evidence of a decreased retinal function after 9 days of treatment. In this way, we were able to develop a retinal degeneration model in vivo to carry out treatment with MEL and observed an increase in the survival percentage of RGCs, showing that BSO-GLUT could not exert an oxidant effect on cells to counteract the effect of MEL. These findings reveal that MEL has a neuroprotective and antiapoptotic effect as evidenced by the reduction of oxidative stress damage. MEL demonstrated in this model makes it a promising neuroprotective agent for the treatment of ocular neurodegenerative diseases when administered locally., (Copyright © 2019 Elsevier Inc. All rights reserved.)

There is a need for new vaccine adjuvant strategies that offer both vigorous antibody and T-cell mediated protection to combat difficult intracellular pathogens and cancer. To this aim, we formulated class-B synthetic oligodeoxynucleotide containing unmethylated cytosine-guanine motifs (CpG-ODN) with a nanostructure (Coa-ASC16 or coagel) formed by self-assembly of 6-0-ascorbyl palmitate ester. Our previous results demonstrated that mice immunized with ovalbumin (OVA) and CpG-ODN formulated with Coa-ASC16 (OVA/CpG-ODN/Coa-ASC16) elicited strong antibodies (IgG1 and IgG2a) and Th1/Th17 cellular responses without toxic systemic effects. These responses were superior to those induced by a solution of OVA with CpG-ODN or OVA/CpG-ODN formulated with aluminum salts. In this study, we investigated the capacity of this adjuvant strategy (CpG-ODN/Coa-ASC16) to elicit CD8 + T-cell response and some of the underlying cellular and molecular mechanisms involved in adaptive response. We also analyzed whether this adjuvant strategy allows a switch from an immunization scheme of three-doses to one of single-dose. Our results demonstrated that vaccination with OVA/CpG-ODN/Coa-ASC16 elicited an antigen-specific long-lasting humoral response and importantly-high quality CD8 + T-cell immunity with a single-dose immunization. Moreover, Coa-ASC16 promoted co-uptake of OVA and CpG-ODN by dendritic cells. The CD8 + T-cell response induced by OVA/CpG-ODN/Coa-ASC16 was dependent of type I interferons and independent of CD4 + T-cells, and showed polyfunctionality and efficiency against an intracellular pathogen. Furthermore, the cellular and humoral responses elicited by the nanostructured formulation were IL-6-independent. This system provides a simple and inexpensive adjuvant strategy with great potential for future rationally designed vaccines.

Objectives: Here, we aimed to assess the pharmacokinetic performance and therapeutic response (anthelmintic efficacy) of an albendazole (ABZ) nano-sized formulation in dogs., Methods: In the pharmacokinetic study, ABZ self-dispersible nanocrystals (SDNCS) and a control formulation were administered orally to healthy dogs (n = 6). The concentrations of the sulphoxide metabolite in plasma were determined by high-performance liquid chromatography. For the anthelmintic efficacy trial, SDNCS and a commercially available formulation of ABZ were given to naturally parasitised dogs. The number of Ancylostoma caninum eggs in the faeces was determined using the McMaster technique., Key Findings: The area under the curve, Tmax and Cmax for the SDNCS were improved compared to the control. The efficacy study showed no statistical differences between the SDNCS and the commercial formulation at the doses of 25 and 12.5 mg/kg. However, significant differences (P < 0.05) between the treatments were found at 6.25 mg/kg (a quarter of the reference dose) with a reduction in the faecal nematode egg counts of 62.0 ± 21.1% and 100 ± 0% for the control and SDNCS, respectively., Conclusions: The improved pharmacokinetic performance observed for the novel formulation of ABZ correlated with an improved in vivo therapeutic response against a model intestinal nematode parasite in dogs., (© 2017 Royal Pharmaceutical Society.)

This work focuses on improving the effectiveness of current therapies against glaucoma by incorporating self-assembled polymers into the ophthalmic formulation. To that end, we first studied the influence of the dispersing medium on the mechanical performance of self-assembling elastin-like (EL) and silk-elastin-like (SEL) hydrogels by conducting rheological tests. These polymers were subsequently incorporated into the antiglaucoma formulation, which contains timolol maleate (TM) as active ingredient, and in vivo tests, namely adhesion tests and intraocular pressure measurements (IOP), were performed in New Zealand rabbits. An enhanced reduction in IOP due to the presence of the polymers was observed. Moreover, differences in the effectiveness between both EL- and SEL-hydrogels, which can be explained on the basis of the different rheological properties displayed by these two systems, were also encountered. The results point to the potential of this system as a basis for the development of an ophthalmic formulation against glaucoma.

Release kinetics of the volatile compounds of oregano EO microcapsules and the relation with the antioxidant activity were studied. Different wall material (WM) to core (C) ratios (1:1 and 2:1; WM:C), addition of colloidal silicon dioxide (CSD); and different storage conditions: 23 °C (room temperature; R) and 4 °C (fridge temperature; F) were evaluated for 90 d. Volatile compounds, total phenolic content (TPC), free radical scavenging activity (FRSA), and Trolox equivalent antioxidant capacity (TEAC) were measured. The formulas 2:1 (WM:C) (R and F) without CSD behaved differently from the rest, exhibited a higher antioxidant activity, and released less amount of volatile compounds after 90 d. These treatments grouped together in the cluster analysis, showing the highest TPC (81.54 mg gallic ac/g), FRSA (8.66%), and TEAC (12.35 μg Trolox/g). The addition of CSD facilitated the released of volatile compounds through storage time and promoted losses in the antioxidant activity. The temperature had a significant effect in most of the evaluated variables. However, this effect was more noticeable in F2 (1:1, CSD)., Practical Application: Oregano essential oil has antioxidant, antimicrobial, and sensory preserving properties. However, it is susceptible to volatilization and is degraded by external factors. Its addition into food matrices is restricted due to low solubility and hydrophobicity. The antioxidant activity of oregano EO is preserved after the process of microencapsulation by spray-drying that extends its stability during storage. Oregano EO microcapsules are an alternative of delivery which protects and extends the shelf life of this essential oil, overcomes stability related limitations and preserves its desirable characteristics allowing these kind of microcapsules to be later incorporated into food products. These microcapsules could be used as a natural additive/flavouring with antioxidant properties., (© 2017 Institute of Food Technologists®.)

The aim of this work was to obtain information concerning the properties of ophthalmic formulations based on hyaluronic-drug ionic complexes, to identify the factors that determine the onset, intensity and duration of the pharmacotherapeutic effect. Dispersions of a complex of 0.5% w/v of sodium hyaluronate (HyNa) loaded with 0.5% w/v of timolol maleate (TM) were obtained and presented a counterionic condensation higher than 75%. For comparison a similar complex obtained with hyaluronic acid (HyH) was also prepared. Although the viscosity of HyNa-TM was significantly higher than that of HyH-TM, in vitro release of TM from both complexes showed a similar extended drug release profile (20-31% over 5h) controlled by diffusion and ionic exchange. Ocular pharmacokinetic study performed in normotensive rabbits showed that HyNa-TM complex exhibited attractive bioavailability properties in the aqueous humor (AUC and Cmax significantly higher and later Tmax) compared to commercial TM eye-drops. Moreover, a more prolonged period of lowered intra-ocular pressure (10h) and a more intense hypotensive activity was observed after instillation of a drop of HyNa-TM as compared to the eye-drops. Such behavior was related to the longer pre-corneal residence times (400%) observed with HyNa-TM complex. No significant changes in rabbit transcorneal permeation were detected upon complexation. These results demonstrate that the ability of HyNa to modulate TM release, together with its mucoadhesiveness related to the viscosity, affected both the pharmacokinetic and pharmacodynamic parameters. The HyNa-TM complex is a potentially useful carrier for ocular drug delivery, which could improve the TM efficacy and reduce the frequency of administration to improve patient compliance., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Control of ovine brucellosis with subcellular vaccines can solve some drawbacks associated with the use of Brucella melitensis Rev.1. Previous studies have demonstrated that the polymeric antigen BLSOmp31 administered by parenteral route was immunogenic and conferred significant protection against B. ovis in rams. Immunization with BLSOmp31 by conjunctival route could be efficient for the induction of mucosal and systemic immune responses. In this work, we evaluated the conjunctival immunization using a thermoresponsive and mucoadhesive in situ gel composed of Poloxamer 407 (P407) and chitosan (Ch) as vaccine delivery system for BLSOmp31 in rams. Serum samples, saliva, lacrimal, preputial and nasal secretions were analyzed to measure specific IgG and IgA antibodies. Cellular immune response was evaluated in vivo and in vitro. Immunization with BLSOmp31-P407-Ch induced high IgG antibody levels in serum and preputial secretions which remained at similar levels until the end of the experiment. Levels of IgG in saliva, lacrimal and nasal secretions were also higher compared to unvaccinated control group but decreased more rapidly. IgA antibodies were only detected in nasal and preputial secretions. BLSOmp31-P407-Ch stimulated a significant cellular immune response in vivo and in vitro. The induction of systemic and local immune responses indicates a promising potential of P407-Ch for the delivery of BLSOmp31 by conjunctival route., (Copyright © 2016. Published by Elsevier B.V.)

Previous studies have demonstrated that parenteral immunization with polymeric antigen BLSOmp31 induced a strong immune response and conferred protection against Brucella ovis in rams. This work describes the development of a novel formulation strategy for the delivery of BLSOmp31 in the nasal mucosa. Chitosan microparticles were prepared by spray-drying technology processes and recombinant chimera BLSOmp31 was loaded by passive adsorption onto chitosan microspheres, which were characterized by means of the evaluation of size, zeta potential, morphology, and loading and release rate of BLSOmp31. The mucoadhesive properties of microspheres were evaluated by studying the interaction between microparticles and mucin. The antigen BLSOmp31 integrity was investigated by SDS-PAGE. The yield of production of spray-drying process was 68.95%. Microspheres had a good sphericity, 1-10 μm of particle size and had a positive charge. The loading capacity was found to be 45.19%. The initial fast release of BLSOmp31 from chitosan microparticles was 60%. The BLSOmp31 integrity was not affected by passive adsorption (ionic interaction). The amount of mucin adsorbed on the surface of CMs-BLSOmp31 was lower than on the surface of blank CMs at neutral pH. In vivo studies were carried out in rams. Intranasal immunization induced systemic and local antibodies. In conclusion, the use of BLSOmp31-loaded chitosan spray-drying microspheres offers a promising way for nasal mucosal vaccination in sheep against brucellosis., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Ivermectin (IVM) is probably one of the most widely used antiparasitic drugs worldwide, and its efficacy is well established. However, slight differences in formulation may change the plasma kinetics, the biodistribution, and in consequence, the efficacy of this compound. The present study focuses on the development of a novel nanocarrier for the delivery of lipophilic drugs such as IVM and its potential application in antiparasitic control. Lipid nanocapsules (LNC) were prepared by a new phase inversion procedure and characterized in terms of size, surface potential, encapsulation efficiency, and physical stability. A complement activation assay (CH50) and uptake experiments by THP-1 macrophage cells were used to assess the stealth properties of this nanocarrier in vitro. Finally, a pharmacokinetics and biodistribution study was carried out as a proof of concept after subcutaneous (SC) injection in a rat model. The final IVM-LNC suspension displayed a narrow size distribution and an encapsulation rate higher than 90 % constant over the evaluated time (60 days). Through flow cytometry and blood permanence measurements, it was possible to confirm the ability of these particles to avoid the macrophage uptake. Moreover, the systemic disposition of IVM in the LNC administered by the SC route was higher (p < 0.05) (1367 ng h/ml) compared to treatment with a commercial formulation (CF) (1193 ng.h/ml), but no significant differences in the biodistribution pattern were found. In conclusion, this new carrier seems to be a promising therapeutic approach in antiparasitic control and to delay the appearance of resistance.

Suramab (SUM) is a new pharmaceutical combination made up of suramine (SUR) and bevacizumab (BVM), which showed a high synergistic effect when administered jointly. As the pharmaceutical vehicle, poloxamer aqueous dispersions were used since this system is able to maintain their fluidity at low temperatures (<15ºC) but which become gel in the corporal environment (>35ºC). In the present study we aimed at evaluating the effect of Poloxamer to prolong the effect of SUM. These formulations were characterized using rheological, biopharmaceutical (drug release) and morphological (SEM) technique. Corneal NV was induced in Sprague Dawley rats Corneal. At 15 days of follow up animals were sacrificed and perfused with black drawing ink. Digital photographs were taken and the area of neovascularisation (ANV) was calculated using the image programmed. The rheological behavior was influenced by the addition of drugs, resulting in a decrease in the gelation temperature (Tsol/gel). Both drugs were released from poloxamer gels by means of an anomalous mechanism. However, BVM was released faster than SUR, with their combination (SUM) to appearing to reduce delivery, probably due to interactions between the drugs or with the polymeric matrix. The in vivo studies showed that SUM-poloxamer gel was able to increase the corneal antiangiogenic effect compared to the SUM solution and BVM alone at 15 days of follow-up. Furthermore no injurious effects were observed in the histological tissue examination after drug administration. The presence of Poloxamer, known to modulate control release of biological agents, seems to have a favorable effect on SUM subconjunctival administered., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A novel ophthalmic formulation based on the ionic complexation between Eudragit E 100 (EU) and flurbiprofen (FB) is proposed. The selected complex composition, named EU-FBH50 Cl50 , had the basic groups of EU completely neutralized with equal molar amounts of FB and HCl. This complex, obtained in the solid state, exhibited a high aqueous compatibility producing a colloidal dispersion with a high positive electrokinetic potential, in which more than 99% of FB was ionically condensed with EU. In bicompartimental Franz cells, FB diffusion from the complex was very slow. However, dispersion in 0.9% NaCl increased the FB release through an ionic exchange, providing an optimal constant rate of delivery. Corneal FB permeation from 0.1% EU-FBH50 -Cl50 dispersed in 0.9% NaCl solution was substantially more effective compared with 0.1% FB solution, EU-FBH50 -Cl50 (Dex), or Tolerane(®) (a marketed formulation). This complex formulation was shown to be innocuous for rabbit ocular tissues because no irritant effects were evidenced., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

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 Ly6C(high) 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 © 2013 Elsevier Ltd. All rights reserved.)

Solid dispersions (SDs) containing the anthelmintic compound albendazole (ABZ) and either Pluronic 188 (P 188) or polyethylene glycol 6000 (PEG 6000) as hydrophilic carriers were formulated. Drug-polymers interactions in solid state were investigated using different techniques. Only a 4% of total ABZ was dissolved at 5 min post-incubation, reaching dissolution rates of 32.8% (PEG 6000) and 69.4% (P 188) in SDs. In this way, P 188 was substantially more efficient as ABZ dissolution promoter in comparison to PEG 6000, especially at the initial stages of the dissolution processes (<30 min). An increased systemic availability (p < 0.001) was obtained when ABZ was administered as ABZ-P 188 SDs, with a 50% enhancement in systemic exposure (AUC values) compared to treatment with an ABZ suspension. Consistently, the Cmax increased 130% (p < 0.001) following treatment with P 188 based SD ABZ formulation. For the ABZ-PEG 6000 SD formulation, the favorable effect on ABZ systemic availability did not reached statistical significance compared to the control group. The study reported here showed the utility of pharmacokinetic assays performed on mice as a model for preliminary drug formulation screening studies.

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 P(app) values (J=1.43 μg/min and P(app)=3.04 cm.s(1)). 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.

Equilibria and release properties of aqueous systems consisting of a set of five non-steroidal anti-inflammatory drugs (AH) complexed with the cationic polymethacrylate Eudragit E 100 (EU) are reported in this study. The composition (EU(AH)(50) (HCl)(50)) having fifty mole percent of each counterion (A(-) and Cl(-)) produces clear, stable aqueous dispersions in which a remarkably high proportion of AH (higher than 98%) is condensed with the PE under the form of ion pairs. This property expands the interval of pH in which AH are aqueous soluble. The set of AH contains members with and without an alpha methyl group (-(CH(3))CH-COOH: Flurbiprofen, Naproxen, Ketoprofen) and (-CH(2)-COOH: Diclofenac, Indomethacin). The proportion of ion pairs in the complexes was lower in the former group. Release of AH from the complexes toward a saline (NaCl 0.9%) solution was assayed in Franz cells. The five complexes behaved as drug carriers that exhibited a slow drug release with a remarkable zero order. In line with the percentages of counterionic condensation observed, release rates from -(CH(3))CH-COOH complexes were clearly higher than those of -CH(2)-COOH ones.

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 Asc16.2·6H(2)O. 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 © 2011 Elsevier B.V. All rights reserved.)

In this work, we report results concerning the study of solid complexes compounded by a cationic polymethacrylate (Eudragit® E100, Eu) and mesalazine (M) (Eu-M(x) complex). The influence of an anionic polyacrylic acid polymer (carbomer, C) on dissolution behavior of M from the complex was evaluated (Eu-M(x) C(y) complex). The dissolution profiles and solvent front movements of solid matrices in different media (water, buffer pH 7.4, 0.9% NaCl) were investigated and ionic interactions among Eu, M, and C were determined through Fourier transform infrared (FT-IR) spectroscopy. For Eu-M(x) complexes, the affinity between M and Eu modulated the delivery of free M in solution, with the dissolution media affecting the delivery rate mainly due to an ionic interchange process between M and anionic electrolytes (i.e., Cl(-)). FTIR spectroscopy allowed the ionic interaction between Eu and M to be verified. The addition of C (Eu-M(x) C(y) ) influenced the dissolution behavior of these matrices. As the amount of C was increased, the release mechanism changed from diffusion (Eu-M(50) ) or anomalous (Eu-M(100)) to zero order (Eu-M(x) C(50)). This variation in rate delivery was also affected by the dissolution media, as occurred with Eu-M(x) complexes. The formation of the gel layer during the dissolution process, as consequence of Eu-M(x) C(y) matrices hydration, was influenced by C amount and dissolution media., (Copyright © 2011 Wiley-Liss, Inc.)

Solids dispersions (SDs) have been proposed as an alternative to improve the dissolution rate of low solubility drugs. SDs containing albendazole (ABZ; 5, 10, 25, and 50% w/w) and Pluronic 188 (P 188) as hydrophilic carrier were formulated. The obtained SDs were assessed in comparison to physical mixtures (PMs). Drug-polymer interactions in solid state were investigated using Fourier-transform infrared spectroscopy, scanning electron microscopy, and X-ray diffraction analysis. No chemical interaction was found between ABZ and poloxamer. The dissolution profiles indicated that ABZ incorporated in SDs and PMs was rapidly released, reaching rapidly the steady state. Increased dissolution rates are usually observed at the highest polymer proportions. However, an opposite effect for SDs as well as for PMs was observed in the assays described here. The systems with the lowest P 188 percentages (SD4, SD3; PM4, PM3) tended to be more effective in increasing the ABZ dissolution rate. Such a result can be attributed to the fact that concentrated aqueous solutions of Poloxamer may form thermo-reversible gels. The physical-mechanical properties indicated that SDs possess improved flow and compacting properties compared to PMs. Thus, ABZ SDs would be more convenient for solid dosage form design and manufacture.

In this work, the design and evaluation of a colonic drug delivery system containing mesalamine (M) is presented. The main goal was to enable M to reach the first part of the colon, where the drug could then be released. To facilitate this, a tablet core was coated with two thin layers. The first compounded by chitosan, which was responsible for core protection in the small intestine until it reached the colon. Once at the colon, microbiological enzymatic activity of the caecal content would degrade the Ch layer, thus triggering drug release. The second layer, the outer one, was compounded with Eudragit L100 (EL), with its function being to avoid the dissolution of the Ch-covered core along the gastro intestinal tract (GIT). In order to achieve a modulated drug release, carbomer P934 (1%) was also included. Dissolution studies showed that the formulation seemed to behave as predicted. The amount of M released from the coated tablet was less than 10% at pH = 1.2 and 6.8. However, when the coated tablet was evaluated in a medium with a caecal content of pH = 7.4, the M delivery was immediately triggered owing to enzymatic activity of the microflora. In this medium, approximately 60% of M was released in a period of 3 h. Although these results are promising, further studies are still necessary to evaluate the possible in vitro/in vivo correlations.

Amiodarone aqueous systems at concentrations C

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(R) formulation (1% w/v brinzolamide) was studied. Formulations were also tested for their effect on the intraocular pressure (IOP) in rabbits. (1)H- and (13)C-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.

Mucoadhesive tablets containing nystatin (10 mg) were evaluated in vivo. The assays were carried out with 12 healthy volunteers and the concentration of nystatin in saliva was determined at different times. Tablets remained attached to the buccal mucosa during 270 min +/- 30 min. No evidence of ulceration or bleeding was observed. Typical appearance of intact human buccal mucosa was seen before and after contact with the tablet. The tablets were well accepted by the volunteers, although most of the volunteers reported a light bitter taste, probably due to nystatin. Concentration of nystatin in saliva was several times higher than MIC over a period of approximately 4.5 h, which was in agreement with the behavior observed in vitro. These results allow us to infer that the administration of these mucoadhesive tablets could be advantageous compared to conventional formulations and mucoadhesive extended-release tablets might produce better therapeutic performance than conventional formulations in the treatment of oral candidosis.

This article reports the development and delivery properties of swellable drug-polyelectrolyte matrices prepared with complexes of the acid form of carboxymethylcellulose (HCMC). Drug-polyelelectrolyte complexes (HCMC-D) were obtained by neutralization of HCMC with two model basic drugs (atenolol and metoclopramide). Characterization through FT-infrared spectroscopy, power X-ray diffraction, and DSC indicates the ionic nature of the interaction between the carboxylic groups of HCMC and the basic group of D. Matrices prepared by compacting (HCMC-D) alone or in a mixture with sodium carboxymethylcellulose were subjected to measurements of solvent up-take, dynamics of swelling, and release kinetics. Delivery rate of mixed matrices is a function of its composition and may be widely modulated. They exhibited anomalous delivery kinetics with Korsmeyer exponent n in the range 0.67-0.87. Experimental results indicate that the erosion of the hydrogel layer is the main delivery process.

The aim of this work was the development of extended release tablets of 500 mg of ciprofloxacin based on swellable drug polyelectrolyte matrices (SDPM). A set of complexes of carbomer, ciprofloxacin and sodium, (CB-Cip)(50)Na( x ), having a molar ratio Cip/CB acid groups of 0.5 and variable proportions of Na(+) was used to prepare SDPM. Characterization of complexes by FT-IR, powder X-ray diffraction and thermal analysis revealed that Cip, in its protonated form, is ionically bonded to the functional groups of CB. Rates of fluid uptake of (CB-Cip)(50)Na( x ) matrices as well as Cip release in simulated gastric fluid were modulated by changes in the proportion of Na(+) incorporated in the complexes. A direct correlation between fluid uptake and delivery rate was observed along the series of matrices. Release rates were modulated from 1.4 mg/min to 25 mg/min in going from (CB-Cip)(50)Na(10) to (CB-Cip)(50)Na(14). The analysis of kinetic data suggest that rates of swelling, ionic pair dissociation and drug diffusion play a role in the kinetic control of delivery. Complexes were satisfactorily prepared and processed together with small amounts of antiadherent and lubricant excipients to obtain a series of extended release SDPM tablets through the current tableting technology processes. Cip release from matrices was widely modulated by the composition of the complexes yielding a flexible system that allows selecting a composition that releases in 120 min 90% of the dose in simulated gastric fluid.

The interaction between a cationic polymethacrylate (Eudragit E, EU) and a set of 7 drugs having acid groups (AH) was studied. Two series of complexes were prepared (EU-AH50 and EU-AH50Cl50), in both 50% of the basic groups of EU were neutralized with AH but in the second, the remaining groups were further neutralized with HCl. These products were stable solid ionic complexes that were characterized through infrared spectroscopy and X-ray power diffraction. All EU-AH50Cl50 at 5-10mg/ml produced clear optically isotropic aqueous dispersions. This result was in line with the increase of the apparent solubility of the low solubility AH assayed. The species distribution, as determined on the complex of diclofenac, showed a degree of counterion condensation as high as 97.9%. The reversibility of the counterion condensation, as well as the affinity between EU and AH, was evaluated through the proton withdrawing effect produced by the ionic exchange generated by titration with NaCl. Besides, drug delivery in bicompartimental Franz cells towards water as receptor medium was very slow. However, it was increased as water was replaced by NaCl solution that upon diffusion generates ionic exchange. Therefore, the EU-AH system behaves as a reservoir of drug able to deliver it in simulated biological fluid.

An isocratic high-performance liquid chromatographic method was developed, optimized and validated for the determination of nystatin in human saliva (UV and fluorescence detection). A reversed-phase Luna C18 column (25 degrees C), with a mobile phase of MeOH, H2O, and DMF (70:20:10, v/v/v), and a flow-rate of 0.8 ml/min were used. The elution time for nystatin was 5.8+/-0.2 min. Calibration curves in human saliva were linear from 0.78 to 50 microg/ml. Limits of quantification were 0.78 microg/ml and 0.75 microg/ml for UV and fluorescence detection, respectively. The accuracy and precision values of intra- and inter-day variation studies were within acceptable limits, according to FDA guidelines. The described method has proved to be useful to give accurate measurements of nystatin in real samples.

This paper deals with the formulation of the mucoadhesive films containing nystatin. The design and formulation of the films were based on the mucoadhesive properties of carbomer 934P (CB) and carboxymethycellulose (NaCMC), and also on the plasticizer properties of polyethyleneglycol 400 (PEG400). A surfactant (ascorbyl palmitate, ASC16) was added to the system to aid in nystatin dispersion. Addition of these last two components produced a significant improvement in physical-mechanical properties (flexibility and strength) as well as an increase in the nystatin release rate. X-ray powder diffraction (XRPD) and scanning electronic microscopy (SEM) were used to evaluate the morphological changes in the films while PEG400 and ASC16 were added to the formulations. Furthermore, the in vitro nystatin profile release was determined.

In this work, pre-formulation studies concerning the design of novel mucoadhesive films have been carried out. The rationality of the design is based on the utilization of mucoadhesive polymers (carbomer and carboxymethylcellulose), a plasticizer (polyethyleneglycol 400, PEG400) and a surfactant (ascorbyl palmitate, ASC16). In the gel preparation, the casting method using water as a solvent was employed. To provide a better understanding of the structural arrangements produced during the casting process, the changes in morphology (Cryo-TEM) and rheology (viscosity) of the film forming gel were evaluated. When PEG400 was included as a plasticizer, a disorder was produced in the network, reflected in the globular structure adopted by the gel and the consequent decrease in viscosity. The addition of ASC16 improved the solubilization of nystatin and provoked a decrease in gel viscosity. However, as water was removed during casting, ASC16 produced a significant increase in the viscosity at the point in which the polymer concentrations were sufficient to strengthen the inter-polymeric interactions, giving rise to a more rigid tri-dimensional network.

This study deals with the development and characterization of the delivery properties of swellable drug-polyelectrolyte matrices (SDPM) of alginic acid (AA). Complexes (AA-D)(x) in solid state were obtained by neutralization of AA with different molar proportions (x) of model basic drugs (D), in which D is atenolol, metoclopramide and propranolol. They were characterized by DSC, IR and X-ray diffraction. Matrices prepared by compaction of (AA-D)(x) alone or in a mixture with sodium alginate (NaAA) were subjected to measurements of solvent up-take, release kinetics and erosion in three media (water, buffer of pH 6.8 and 0.01 M HCl). In addition, the dynamics of swelling was also evaluated. All SDPM assayed exhibited a remarkable zero order of delivery in water and buffer of pH 6.8 and also in two-step delivery experiments: 2 h in acid medium followed by a second step at pH 6.8. Experimental results indicate that the erosion of the hydrogel layer is the main delivery process. Delivery rate, can be modulated either by varying the composition of (AA-D)(x) or by diluting it with NaAA.

6-O-Ascorbic acid alkanoates (ASCn) are amphiphilic molecules having physical-chemical properties that depend on the alkyl chain length. The derivatives of low molecular weight (n < 11) have enough aqueous solubility to produce self-assemblies at room temperature ( approximately 25 degrees C), while those with longer alkyl chains possess a critical micellar temperature (CMT) higher than 30 degrees C. At higher temperatures (T degrees > CMT), ASCn aqueous suspensions turn into either micellar solutions or gel phases, depending on the length of the hydrophobic chain. On cooling, coagels are produced, which possess a lamellar structure that exhibit sharp X-ray diffraction patterns and optical birefringence. The semisolid consistency of such coagels is an interesting property to formulate dermatological pharmaceutical dosage forms able to solubilize and stabilize different drugs. The objective of the present study was the evaluation of the enhancing permeation effect of ASCn with different chain lengths and to correlate permeability changes with histological effects. With this purpose, ASCn coagels containing anthralin (antipsoriasic drug) or fluorescein isothiocyanate (FITC, hydrophobic fluorescent marker) were assayed on rat skin (ex vivo) and mice skin (in vivo), respectively. Also, histological studies were performed aimed at detecting some possible side effects of ASCn. No inflammatory cellular response was observed in the skin when ASCn coagels were applied, suggesting non-irritating properties. Light microscopy indicated slight disruption and fragmentation of stratum corneum. The penetration of ASCn through rat skin epidermis was very fast and quantitatively significant. The permeation of anthralin was significantly increased when the drug was vehiculized in ASCn coagels, compared to other pharmaceutical systems. The results indicated that ASC12 seems to have the highest enhancing effect on FITC permeation. ASC12 appears to be the compound that possesses the highest capacity to enhance the penetration of the drugs. Furthermore, it has the highest permeation of the serie.

The objective of the study is to develop and characterize the delivery properties of swellable drug-polyelectrolyte matrices (SDPM). Solid complexes (C-D)X of carbomer (C) neutralized with different proportions of model basic drugs (D), in which D is atenolol, lidocaine, and metoclopramide, and X=25, 50, 75 and 100 mol of D per 100 equivalents of carboxylic groups of C, were prepared and characterized by DSC-TG, IR, and X-ray diffraction studies. Mechanistic studies with hydrophilic and hydrophobic basic drugs were conducted to explore the drug release patterns of SDPM. Besides, release and up-take studies were carried out in water and NaCl solution to examine the influence of ionic effects. The authors concluded that drugs can be loaded in a high proportion on to the polymer and therefore the resulting (C-D) material could be diluted with other polymers to modulate delivery properties of SDPM. Matrices of atenolol and lidocaine exhibited robust delivery properties with regard to change in proportion of loading D.

With the purpose of getting information about the factors that determine the affinity between basic drugs (B) and the acid form of carboxymethylcellulose (HCMC), the constant K(ip) for the equilibrium HCMC + B <==> CMC- BH+ was measured using a set of nine model B. A linear free energy relationship (LFER) was developed through a multiple correlation of log K(ip) against (pKa + log PC), in which the octanol-water partition coefficient (PC) was introduced as an indicator of the hydrophilicity of B. Both magnitudes, pKa and log PC, contribute to a rise in log K(ip). In addition, water uptake and drug delivery were assayed with the product of neutralization of HCMC with atenolol, which was easily wetted, and the drug-HCMC interaction was found essentially reversible.

In vitro mucoadhesion, water uptake, and drug release of nystatin (N) from matrices of carbomer (C) and lyophilized carbomer sodium salt (CNaL) mixtures were evaluated. Matrices with different ratios C:CNaL were prepared by direct compression. Commercial C as well as lyophilized powder (CL) were used. In vitro mucoadhesion increased as the proportion of C in the matrix was raised. The same effect was observed when C was replaced by CL. Matrices in which C was replaced by CL showed an increase of both water uptake and release rates. Besides, the release of N from matrices CL:CNaL exhibited a kinetics with Super Case II (n>1) mechanism. However, for C:CNaL matrices, drug release was slower and exhibited a biphasic profile with a first stage characterized by either an anomalous (n<1, for C>or=50%) or a Case II (n approximately 1.0, C<50%) mechanisms. After that period, the mechanism changed to Super Case II transport (n>1).

Carbomer (C) and procaine (P) were selected respectively as models of polyelectrolyte (PE) and basic drug (B) of low stability in aqueous solution. The purpose of this investigation was to test if a (C-P) aqueous system provides a microenvironment in which P is less exposed to hydroxyl ion catalyzed degradation, its main degradation pathway over a wide pH range. It was determined that in (C-P) a high fraction of P was present in the form of ion pairs [RCOO-PH+] with the carboxylate groups of C. The [RCOO-PH+] fraction was above 97% for compositions containing higher than 50 mol% of P. The chemical stability of C-P was assayed at two selected pHs (7.5 and 8.5) in comparison with conventional reference solutions (RS) without C. Procaine in (C-P) was 4.2 and 6.2 times more stable than in its respective RS at the two conditions assayed. The stabilizing factor was calculated as the ratio of the rate constants k(obs)(RS)/k(obs)(C-P).Since C-B systems exhibit negative electrokinetic potential that attracts positive ions such as (H+) and repels negative ones such as (OH(-)), the stabilizing effect would be associated with the higher acidity of (C-P) environment, in which PH+ molecules attached to the PE should also have lower kinetic energy than those in the bulk medium.