RESUMEN
Posterior segment eye diseases (PSEDs) including age macular degeneration (AMD) and diabetic retinopathy (DR) are amongst the major causes of irreversible blindness worldwide. Due to the numerous barriers encountered, highly invasive intravitreal (IVT) injections represent the primary route to deliver drugs to the posterior eye tissues. Thus, the potential of a more patient friendly topical route has been widely investigated. Mucoadhesive formulations can decrease precorneal clearance while prolonging precorneal residence. Thus, they are expected to enhance the chances of adherence to corneal and conjunctival surfaces and as such, enable increased delivery to the posterior eye segment. Among the mucoadhesive polymers available, chitosan is the most widely explored due to its outstanding mucoadhesive characteristics. In this review, the major PSEDs, their treatments, barriers to topical delivery, and routes of topical drug absorption to the posterior eye are presented. To enable the successful design of mucoadhesive ophthalmic drug delivery systems (DDSs), an overview of mucoadhesion, its theory, characterization, and considerations for ocular mucoadhesion is given. Furthermore, chitosan-based DDs that have been explored to promote topical drug delivery to the posterior eye segment are reviewed. Finally, challenges of successful preclinical to clinical translation of these DDSs for posterior eye drug delivery are discussed.
RESUMEN
Fermented liquid feeding has proved beneficial for weaner pigs; however, there is limited research on its effect on the growth and feed conversion efficiency (FCE) of grow-finisher pigs. Microbial decarboxylation of amino acids is associated with whole diet fermentation, while wet/dry and liquid feeding reportedly improve growth compared with dry feeding. The objective of this study was to determine the effect of wet/dry feeding and fresh, fermented whole diet, and fermented cereal liquid feeding on pig growth, feed efficiency, and carcass quality in grow-finisher pigs. Pigs were allocated to one of four dietary treatments in two experiments: 1) Single-space wet/dry feeders (WET/DRY), 2) Fresh liquid feeding (FRESH), 3) Fermented cereal liquid feeding where the cereal fraction (38% barley, 40% wheat) of the diet was fermented prior to feeding (FERM-CER), and 4) Fermented whole diet liquid feeding where the whole diet was fermented prior to feeding (FERM-WH). In exp. 1, pigs were fed the experimental diets for 68 d prior to slaughter (29.8 kg ± 0.92 SE to 102.3 kg ± 0.76 SE). Overall, average daily gain (ADG) was 1,094, 1,088, 1,110, and 955 g/d (SE = 13.0; P < 0.001) and FCE was 2.26, 2.37, 2.40, and 2.88 (SE = 0.031; P < 0.001) for treatments one through four, respectively. Pigs fed FERM-WH were lighter at slaughter than pigs fed the other three treatments (P < 0.001). In exp. 2, pigs were on treatment for 26 d prior to slaughter (85.3 kg ± 1.69 SE to 117.5 kg ± 0.72 SE). Overall, ADG in exp. 2 was 1,103, 1,217, 1,284, and 1,140 g/d (SE = 27.9; P < 0.01) and FCE was 2.78, 2.99, 2.95, and 3.09 g/g (SE = 0.071; P = 0.05), for treatments one through four, respectively. There were no significant differences observed between treatments for apparent total tract digestibility of dry matter, organic matter, nitrogen, gross energy, or ash. Higher lactic acid bacteria counts and lower Enterobacteriaceae counts and pH were observed in FERM-CER and FERM-WH compared with WET/DRY and FRESH. Ethanol concentrations were almost 4-fold higher in FERM-CER troughs than FRESH troughs and 5-fold higher in FERM-WH than FRESH troughs. To conclude, FERM-WH resulted in poorer growth and FCE compared with WET/DRY, FRESH, and FERM-CER, probably due to amino acid degradation and a loss in gross energy found in FERM-WH.
Asunto(s)
Alimentación Animal/análisis , Dieta/veterinaria , Microbiología de Alimentos , Porcinos , Alimentación Animal/microbiología , Alimentación Animal/normas , Animales , Grano Comestible , Enterobacteriaceae , Femenino , Fermentación , Tracto Gastrointestinal , Hordeum/química , Masculino , Triticum/químicaRESUMEN
A dispersive liquid-liquid microextraction (DLLME) method, combined with HPLC-UV detection, was developed for the extraction and preconcentration of δ-tocopherol from bovine milk. This method was used to study the effect of supplementing cow feed with the seaweed Ascophyllum nodosum on vitamin content in milk. The optimal experimental conditions were determined: 200⯵L of chloroform (extraction solvent), 1.0â¯mL of ethanol (dispersive solvent), 5â¯mL of water (aqueous phase). Under these optimal conditions the DLLME method provided linearity in the range 0.01⯵g/mL to 8⯵g/mL with R2 values of 0.998. Limit of detection (LOD) was 0.01⯵g/mL, while the enrichment factor was 89. Cow feed that was supplemented with Ascophyllum nodosum was shown to increase δ-tocopherol levels from 3.82⯵g/mL to 5.96⯵g/mL.
Asunto(s)
Alimentación Animal , Suplementos Dietéticos , Microextracción en Fase Líquida/métodos , Leche/química , Algas Marinas , Tocoferoles/análisis , Animales , Bovinos , Cromatografía Líquida de Alta Presión , Límite de Detección , Modelos Lineales , Reproducibilidad de los Resultados , Proyectos de Investigación , Tocoferoles/química , Tocoferoles/aislamiento & purificaciónRESUMEN
Dispersive liquid-liquid microextraction (DLLME) was used prior to gas chromatography flame ionization detection (GC-FID) for the extraction of five fatty acids from milk taken from cows with different body condition scores. Optimum extraction conditions were: 300⯵L of chloroform (extraction solvent), and 1â¯mL methanol (dispersive solvent). The procedure was optimised using Design of Experiments (DoE). The analytes were separated on a GC capillary column containing a polyethylene glycol stationary phase (15â¯mâ¯×â¯0.53â¯mmâ¯×â¯1.2⯵m). Enrichment factors were in the range of 8-15 and limit of detection (LOD) was 0.04⯵g/mL. Calibration graphs showed good linearity with coefficients of determination higher than 0.994% and relative standard deviations lower than 7%. This method provided a simple and rapid derivatisation and extraction method for the determination of fatty acids in bovine milk. It showed that there was a significant difference in the palmitic acid content of milk from cows that had an optimum body condition score (10.85â¯mg/mL) compared to cows that had a high body condition score (5.73â¯mg/mL).
Asunto(s)
Ácidos Grasos/análisis , Microextracción en Fase Líquida/métodos , Leche/química , Animales , Bovinos , Cromatografía de Gases , Ácidos Grasos/química , Ácidos Grasos/aislamiento & purificación , Límite de Detección , Modelos Lineales , Reproducibilidad de los ResultadosRESUMEN
Mucoadhesion is the process of binding a material to the mucosal layer of the body. Utilising both natural and synthetic polymers, mucoadhesive drug delivery is a method of controlled drug release which allows for intimate contact between the polymer and a target tissue. It has the potential to increase bioavailability, decrease potential side effects and offer protection to more sensitive drugs such as proteins and peptide based drugs. The thiolation of polymers has, in the last number of years, come to the fore of mucoadhesive drug delivery, markedly improving mucoadhesion due to the introduction of free thiol groups onto the polymer backbone while also offering a more cohesive polymeric matrix for the slower and more controlled release of drug. This review explores the concept of mucoadhesion and the recent advances in both the polymers and the methods of thiolation used in the synthesis of mucoadhesive drug delivery devices.
Asunto(s)
Sistemas de Liberación de Medicamentos , Polímeros/química , Compuestos de Sulfhidrilo/química , Adhesividad , Humanos , Membrana Mucosa/químicaRESUMEN
The thiolation of polyallylamine (PAAm) for use in mucoadhesive drug delivery has been achieved. PAAm was reacted with different ratios of Traut's reagent, yielding products with thiol contents ranging from 134-487µmol/g. Full mucoadhesive characterisation of the thiolated PAAm samples was conducted using swelling studies, mucoadhesive testing on porcine intestinal tissue and rheology. Both swelling and cohesive properties of the thiolated PAAm products were vastly improved in comparison to an unmodified PAAm control. The swelling abilities of the thiolated samples were high and the degree of thiolation of the products affected the initial rate of swelling. High levels of mucoadhesion were demonstrated by the thiolated PAAm samples, with adhesion times of greater than 24h measured for all three samples and, thus, thiol content did not appear to influence mucoadhesion. Rheological studies of the thiolated PAAm samples showed an increase in G' and Gâ³ values upon the addition of a mucin solution which was not observed in the unmodified control, again highlighting the mucoadhesive interactions between these thiolated polymers and mucin. The synthesis of thiolated PAAm by reaction with Traut's reagent and resulting mucoadhesive properties demonstrates its potential for use a mucoadhesive drug delivery device.
Asunto(s)
Adhesividad , Sistemas de Liberación de Medicamentos , Poliaminas/química , Compuestos de Sulfhidrilo/química , Animales , Química Farmacéutica/métodos , Mucosa Intestinal/metabolismo , Mucinas/metabolismo , Poliaminas/síntesis química , Polímeros/síntesis química , Polímeros/química , Reología , Compuestos de Sulfhidrilo/síntesis química , Porcinos , Factores de TiempoRESUMEN
Synthetic polymers, polyacrylic acid (PAA) and polyallylamine (PAAm), were thiolated using different methods of thiolation. Both polymers resulted in comparable thiol contents, thus allowing for the direct comparison of mucoadhesive and cohesive properties between the well-established thiolated PAA and the more novel thiolated PAAm. Thiolation of both polymers improved the swelling ability and the cohesive and mucoadhesive properties in comparison to unmodified control samples. In this study, it was shown that the swelling abilities of the thiolated PAAm sample were far greater than that of the thiolated PAA sample which, in turn, affected the drug release profile of the thiolated PAAm sample. Importantly, however, the mucoadhesive properties of thiolated PAAm were equivalent to that of the thiolated PAA sample as demonstrated by both the adhesion times on porcine intestinal tissue as measured by the rotating cylinder method and by rheological studies with a mucin solution. This study demonstrates the potential thiolated polyallylamine has as a mucoadhesive drug delivery device.
Asunto(s)
Resinas Acrílicas/química , Resinas Acrílicas/metabolismo , Mucosa Intestinal/metabolismo , Poliaminas/química , Poliaminas/metabolismo , Adhesividad , Animales , Técnicas de Cultivo de Órganos , Polímeros/química , Polímeros/metabolismo , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/metabolismo , PorcinosRESUMEN
Using a novel two-step approach, the thiolation of gelatin for mucoadhesive drug delivery has been achieved. The initial step involved the amination of native gelatin via an amine to carboxylic acid coupling reaction with ethylene diamine, followed by thiolation with Traut's reagent. The resulting thiolated product showed an increase in thiol content of up to 10-fold in comparison with control gelatin samples. Improved cohesion and mucoadhesion in comparison with unmodified and control gelatin samples was also observed. This reaction process was observed to be influenced by both the temperature and the pH of the amination reaction, affecting both amine content and product yield. Swelling ability, cohesion and mucoadhesion were all observed to be strongly dependent on the thiol content of the samples but also, importantly, the molecular weight (MW) of the gelatin used. Gelatin with a MW of 20-25 kDa proved to be optimal in creating this novel mucoadhesive gelatin material.
Asunto(s)
Sistemas de Liberación de Medicamentos , Gelatina/química , Mucosa Intestinal/metabolismo , Polímeros/química , Compuestos de Sulfhidrilo/química , Adhesividad , Aminación/efectos de los fármacos , Animales , Bovinos , Reactivos de Enlaces Cruzados/química , Reactivos de Enlaces Cruzados/farmacología , Etilenodiaminas/química , Etilenodiaminas/farmacología , Gelatina/metabolismo , Calor , Concentración de Iones de Hidrógeno , Imidoésteres/química , Imidoésteres/farmacología , Indicadores y Reactivos/química , Indicadores y Reactivos/farmacología , Microscopía Electrónica de Rastreo , Peso Molecular , Polímeros/síntesis química , Compuestos de Sulfhidrilo/síntesis química , Propiedades de Superficie , Sus scrofa , Agua/análisisRESUMEN
Macular pigment (MP) is composed of lutein (L), zeaxanthin (Z) and meso-zeaxanthin (MZ). The present study reports on serum response to three different MP supplements in normal subjects (n 27) and in subjects with age-related macular degeneration (AMD) (n 27). Subjects were randomly assigned to: Group 1 (20 mg L and 2 mg Z), Group 2 (10 mg L, 2 mg Z and 10 mg MZ) or Group 3 (3 mg L, 2 mg Z and 17 mg MZ). Serum carotenoids were quantified at baseline, and at 4 and 8 weeks using HPLC. Response data for normal and AMD subjects were comparable and therefore combined for analysis. We report response as the average of the 4- and 8-week concentrations (saturation plateau). Serum L increased significantly in Group 1 (0·036 µmol/l per mg (269 %); P< 0·001) and Group 2 (0·079 µmol/l per mg (340 %); P< 0·001), with no significant change in Group 3 (0·006 µmol/l per mg (7 %); P= 0·466). Serum Z increased significantly in Group 1 (0·037 µmol/l per mg (69 %); P= 0·001) and Group 2 (0·015 µmol/l per mg (75 %); P< 0·001), with no significant change in Group 3 ( − 0·0002 µmol/l per mg ( − 6 %); P= 0·384). Serum MZ increased significantly in Group 1 (0·0094 µmol/l (absolute value); P= 0·015), Group 2 (0·005 µmol/l per mg; P< 0·001) and Group 3 (0·004 µmol/l per mg; P< 0·001). The formulation containing all three macular carotenoids (Group 2 supplement) was the most efficacious in terms of achieving the highest combined concentration of the three MP constituent carotenoids in serum, thereby potentially optimising the bioavailability of these compounds for capture by the target tissue (retina).
Asunto(s)
Suplementos Dietéticos , Luteína/farmacología , Degeneración Macular/sangre , Retina/metabolismo , Xantófilas/farmacología , Anciano , Disponibilidad Biológica , Método Doble Ciego , Femenino , Humanos , Luteína/sangre , Degeneración Macular/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Valores de Referencia , Xantófilas/sangre , ZeaxantinasRESUMEN
A powerful method utilising direct probe thermal desorption GC-MS is presented for the study of molecularly imprinted polymers (MIPs). A series of 2-aminopyridine (2-apy)-imprinted methacrylic acid-ethyleneglycol dimethacrylate (MAA-EGDMA) copolymers were prepared under identical conditions but with varying amounts of EGDMA (crosslinking monomer). The use of appropriate temperature programmes permitted template removal, and the subsequent assessment of polymer affinity and specificity, all of which were found to be dependent on polymer composition and morphology. The system was sufficiently sensitive to identify a specific response of imprinted polymers over nonimprinted counterparts. Correlations were found to exist between thermal desorption analysis and solution phase binding, which was assessed by UV spectroscopy, where specificity was found to diminish with decreasing EGDMA concentration. This was attributed to the increased number of free carboxyl groups in those polymers containing a lower percentage of EGDMA. Thermal desorption profiles obtained for the analyte were found to be unaffected by the physical and chemical properties of the solvent used for analyte reloading.
Asunto(s)
Reactivos de Enlaces Cruzados/análisis , Reactivos de Enlaces Cruzados/química , Cromatografía de Gases y Espectrometría de Masas/métodos , Impresión Molecular/métodos , Polímeros/análisis , Polímeros/química , Temperatura , Nitrógeno/química , Porosidad , Sensibilidad y Especificidad , Soluciones , SolventesRESUMEN
A novel thermal desorption technique using a direct-probe device (Chromatoprobe) attached to a gas chromatograph-mass spectrometer is presented for the thermal pretreatment, characterisation and analysis of molecularly imprinted polymers. The technique is demonstrated as effective for the removal of volatile materials, including template and unreacted monomers, from methacrylic acid-ethylene glycol dimethacrylate copolymers imprinted with 2-aminopyridine. Mass spectrometry is a powerful technique for polymer bleed characterisation. Thermal desorption studies on reloaded template and related compounds are reported as a means of assessing polymer morphology, specific binding by imprinted polymers compared with reference non-imprinted polymers and selective binding by an imprinted polymer for its template. Calibration studies on the thermal desorption technique using an internal standard are presented with R(2) > 0.999. The technique provides a novel method for assessment of polymer thermal stability, composition and morphology.
RESUMEN
A systematic cross-selectivity study involving a series of structurally related N-methylated and non-methylated substituted pyridines was performed with the aim of evaluating the parameters responsible for template receptor binding in molecularly imprinted polymers. Variation in binding of substrate structure permitted evaluation of the steric restraints of the imprinted cavity. The electrostatic effects, primarily hydrogen-bonding, were investigated through rebinding in chloroform and acetonitrile. All species were non-covalently imprinted in thermoinduced methacrylic acid-ethylene glycol dimethacrylate co-polymers. Evaluation of template properties indicate that a correlation exists between non-specific binding and template basicity for a series of structural isomers. A correlation between non-specific binding and hydrophobicity was also identified for templates increasing in alkyl character. However no overall correlation was observed, as it was speculated that these factors may be competing. All species imprinted, with the exception of 2-dimethylaminopyridine, produced a selective response for the template species. Varying degrees of cross-selectivity were observed for each imprinted polymer. Polymers imprinted with templates of higher basicity demonstrated a greater degree of cross-selectivity relative to those of lower basicity. While overall binding was reduced in acetonitrile relative to chloroform, specificity was increased. This highlights the intrinsic difference in binding sites within imprinted and non-imprinted sites of the polymer. Finally, while the ability of the template species to form a co-operative interaction may be advantageous in producing a selective imprint it is not a prerequisite. For species based on this co-operative interaction the steric environment in the immediate proximity to the binding functionalities are critical to recognition. Steric hindrance of non-functionally active groups can dramatically impair the formation of interactions.