Screening, Synthesis, and Characterization of a More Rapidly Dissolving Celecoxib Crystal Form.

The prevalence of poor solubility in active pharmaceutical ingredients (APIs) such as celecoxib (CEL) is a major bottleneck in the pharmaceutical industry, leading to a low concentration gradient, poor passive diffusion, and in vivo failure. This study presents the synthesis and characterization of a new cocrystal of the API CEL. CEL is a nonsteroidal anti-inflammatory drug used for the treatment of osteoarthritis and rheumatoid arthritis. Computational screening was completed for CEL against a large library of generally recognized as safe (GRAS) coformers, based on molecular complementarity and hydrogen bond propensity (HBP). The generated list of 17 coformers with a likelihood for cocrystallization with CEL were experimentally screened using four techniques: liquid-assisted grinding (LAG), solvent evaporation (SE), gas antisolvent crystallization (GAS), and supercritical enhanced atomization (SEA). One new crystalline form was isolated, employing the liquid coformer N-ethylacetamide (NEA). This novel form, celecoxib-di-N-ethylacetamide (CEL·2NEA), was characterized by a variety of different techniques. The crystal structure was determined through single-crystal X-ray diffraction. Both NEA molecules are evolved from the crystal structure at a desolvation temperature of approximately 65 °C. The CEL·2NEA cocrystal exhibited a dissolution rate, with more than a twofold improvement in comparison to as-received CEL after only 15 min.

Solid-state and particle size control of pharmaceutical cocrystals using atomization-based techniques.

Poor bioavailability and aqueous solubility represent a major constraint during the development of new API molecules and can influence the impact of new medicines or halt their approval to the market. Cocrystals offer a novel and competitive advantage over other conventional methods with respect towards the substantial improvement in solubility profiles relative to the single-API crystals. Furthermore, the production of such cocrystals through atomization-based methods allow for greater control, with respect to particle size reduction, to further increase the solubility of the API. Such atomization-based methods include supercritical fluid methods, conventional spray drying and electrohydrodynamic atomization/electrospraying. The influence of process parameters such as solution flow rates, pressure and solution concentration, in controlling the solid-state and final particle size are discussed in this review with respect to atomization-based methods. For the last decade, literature has been attempting to catch-up with new regulatory rulings regarding the classification of cocrystals, due in part to data sparsity. In recent years, there has been an increase in cocrystal publications, specifically employing atomization-based methods. This review considers the benefits to employing atomization-based methods for the generation of pharmaceutical cocrystals, examines the most recent regulatory changes regarding cocrystals and provides an outlook towards the future of this field.

Investigation of the potential for a simplified exposure tool in medical nutrition (SETIM) to minimise exposures to sweeteners in young patients aged 1-3 years with PKU and CMPA.

Children with phenylketonuria (PKU) and severe cow's milk protein allergy (CMPA) consume prescribed, specially formulated, foods for special medical purposes (FSMPs) in addition to having restricted intake of normal foods. These vulnerable patients are exposed to artificial sweeteners from the consumption of a combination of both free and prescribed foods. Young patients with PKU and CMPA aged from 1 to 3 years have a higher risk of exceeding the acceptable daily intake (ADI) for sweeteners than age-matched healthy children. A probabilistic modelling approach has been adapted successfully to assess the exposure of young patients with PKU and CMPA to low-calorie sweeteners. To assist professionals in the screening and formulation of foods containing food additives for such patients, a simplified exposure method/tool has been developed. The tool is intended to ensure that total dietary exposure can be considered. The simplified tool is not intended to replace the probabilistic model but may be used as a screening tool to determine if further investigation on exposure is warranted. The aim of this study was to develop and validate this simplified exposure tool to support those currently used by healthcare professionals (HCPs) using data available from the probabilistic modelling of exposure in young children with PKU and CMPA. The probabilistic model does not allow for swift screening of exposure scenarios nor is the present EFSA Food Additive Intake Assessment Model (FAIM) fully suitable for application to medical foods. The simplified exposure tool in medical nutrition (SETIM) reported here is both reliable and consistent and provides additive usage levels which minimise regular exposure above the ADI in patients. In addition to the usefulness of SETIM for the medical nutrition industry, the tool has the potential to enhance the practice of evidence-based medical nutrition by official risk assessment bodies, registration authorities and healthcare professionals.

Predictive modelling of the exposure to steviol glycosides in Irish patients aged 1-3 years with phenylketonuria and cow's milk protein allergy.

Children with Phenylketonuria (PKU) and severe cow's milk protein allergy (CMPA) consume prescribed, specially formulated, foods for special medical purposes (FSMPs) as well as restricted amounts of normal foods. These patients are exposed to artificial sweeteners from the consumption of a combination of free and prescribed foods. Young patients with PKU and CMPA have a higher risk of exceeding acceptable daily intakes (ADI) for additives than age-matched healthy children. A predictive modelling approach has been adapted successfully to assess the additive exposure of young patients with PKU and CMPA to artificial sweeteners. Steviol glycosides (E960) are at various stages of regulatory approval for the various food categories in the EU but are not as yet permitted for use in products intended for young children. The aim of this study was to predict potential steviol glycoside exposure in young children with PKU and CMPA considering the potential for future provisions for the use of this sweetener. The recent introduction of steviol glycosides means that no exposure data are available for children with CMPA and PKU. Food consumption data were derived from the food consumption survey data of healthy young children in Ireland from the National Preschool and Nutrition Survey (NPNS, 2010-11). Specially formulated amino acid-based FSMPs are used to replace whole or milk protein foods and were included in the exposure model to replace restricted foods. The recommendations to ensure adequate protein intake in these patients were used to determine FSMP intake. Exposure assessment results indicated that the maximum permitted level (MPL) for FSMPs would warrant careful consideration to avoid exposures above the ADI. These data can be used to inform recommendations for the medical nutrition industry.

Longitudinal modelling of the exposure of young UK patients with PKU to acesulfame K and sucralose.

Artificial sweeteners are used in protein substitutes intended for the dietary management of inborn errors of metabolism (phenylketonuria, PKU) to improve the variety of medical foods available to patients and ensure dietary adherence to the prescribed course of dietary management. These patients can be exposed to artificial sweeteners from the combination of free and prescribed foods. Young children have a higher risk of exceeding acceptable daily intakes (ADI) for additives than adults, due to higher food intakes per kg body weight. Young patients with PKU aged 1-3 years can be exposed to higher levels of artificial sweeteners from these dual sources than normal healthy children and are at a higher risk of exceeding the ADI. Standard intake assessment methods are not adequate to assess the additive exposure of young patients with PKU. The aim of this study was to estimate the combination effect on the intake of artificial sweeteners and the impact of the introduction of new provisions for an artificial sweetener (sucralose, E955) on exposure of PKU patients using a validated probabilistic model. Food consumption data were derived from the food consumption survey data of healthy young children in the United Kingdom from the National Diet and Nutrition Survey (NDNS, 1992-2012). Specially formulated protein substitutes as foods for special medical purposes (FSMPs) were included in the exposure model to replace restricted foods. Inclusion of these protein substitutes is based on recommendations to ensure adequate protein intake in these patients. Exposure assessment results indicated the availability of sucralose for use in FSMPs for PKU leads to changes in intakes in young patients. These data further support the viability of probabilistic modelling as a means to estimate food additive exposure in patients consuming medical nutrition products.

Probabilistic modelling to assess exposure to three artificial sweeteners of young Irish patients aged 1-3 years with PKU and CMPA.

The choice of suitable normal foods is limited for individuals with particular medical conditions, e.g., inborn errors of metabolism (phenylketonuria - PKU) or severe cow's milk protein allergy (CMPA). Patients may have dietary restrictions and exclusive or partial replacement of specific food groups with specially formulated products to meet particular nutrition requirements. Artificial sweeteners are used to improve the appearance and palatability of such food products to avoid food refusal and ensure dietary adherence. Young children have a higher risk of exceeding acceptable daily intakes for additives than adults due to higher food intakes kg-1 body weight. The Budget Method and EFSA's Food Additives Intake Model (FAIM) are not equipped to assess partial dietary replacement with special formulations as they are built on data from dietary surveys of consumers without special medical requirements impacting the diet. The aim of this study was to explore dietary exposure modelling as a means of estimating the intake of artificial sweeteners by young PKU and CMPA patients aged 1-3 years. An adapted validated probabilistic model (FACET) was used to assess patients' exposure to artificial sweeteners. Food consumption data were derived from the food consumption survey data of healthy young children in Ireland from the National Preschool and Nutrition Survey (NPNS, 2010-11). Specially formulated foods for special medical purposes were included in the exposure model to replace restricted foods. Inclusion was based on recommendations for adequate protein intake and dietary adherence data. Exposure assessment results indicated that young children with PKU and CMPA have higher relative average intakes of artificial sweeteners than healthy young children. The reliability and robustness of the model in the estimation of patient additive exposures was further investigated and provides the first exposure estimates for these special populations.

Differential effects of mixtures of cholesterol oxidation products on bovine aortic endothelial cells and human monocytic U937 cells.

Cholesterol oxidation products or oxysterols are of interest due to their hypothesized role in the development of atherosclerosis. The objective of the present study was to assess the cytotoxic effects of mixtures of oxysterols: 25-hydroxycholesterol (25-OHC), 7beta-hydroxycholesterol (7beta -OHC), and cholesterol-5beta,6beta -epoxide (beta -epox) on two cell types associated with the atherosclerotic process, bovine aortic endothelial (BAE) cells and human monocytic U937 cells. Cells were exposed to 25-OHC, 7beta -OHC, or beta -epox, or equimolar mixtures (30 mu M) of 25-OHC and 7beta -OHC, 25-OHC and beta-epox, or 7beta-OHC and beta -epox for 48 h. Cell viability was assessed using the fluorescein diacetate/ethidium bromide (FDA/ EtBr) assay and nuclear morphology following staining with Hoechst 33342. 25-OHC was the least toxic of the oxysterols and did not induce apoptosis in either cell line. Both 7beta-OHC and beta -epox treatments were cytotoxic and induced apoptosis in the cells. Cotreatment with 25-OHC did not alter the toxicity of 7beta -OHC and beta -epox in U937 cells but did decrease the percentage apoptotic cell death. In contrast, in the BAE cells cotreatment with 25-OHC had a slight protective effect on 7beta -OHC and beta-epox-induced toxicities and a marked decrease in apoptotic cell death. The 7beta -OHC and beta -epox mixture induced a significant increase in apoptotic cell death in U937 cells but decreased this mode of cell death in the BAE cells. The effects of oxysterols on glutathione levels also differed between the cells with changes noted in U937 and not in BAE cells. Results demonstrate interactive effects when oxysterols are studied as mixtures rather than single compounds in vitro.