Distribution of benzalkonium chloride into the aqueous phases of submicron dispersed systems: emulsions, aqueous lecithin dispersion and nanospheres.

Partitioning of benzalkonium chloride (BAC) into the aqueous phases of submicron dispersed systems such as submicron emulsions, aqueous lecithin dispersion (WLD), and suspension of nanospheres (NLC) was studied. The aqueous phases of the investigated systems were obtained by ultracentrifugation and subsequently were subjected to ultrafiltration, which procedure allowed distinguishing between the fractions of free benzalkonium chloride (w) and those incorporated in the liposomal and micellar region (wlm). The fractions present in the oily phase and in the interphase of submicron emulsions were calculated. Despite the various composition of the investigated formulations and the initial concentration of BAC, w values were very small at 0.2-8.0%. The wlm value in submicron emulsions was increased by increasing the total concentration of preservative from 29.0 to 42.0%. Using polysorbate 80 instead of lecithin resulted in a distribution of BAC to aqueous-liposomal-micellar phase that was twice as high. The very low concentration of antimicrobial active form of benzalkonium chloride was analyzed in the aqueous phase of emulsions stabilized with lecithin as well as in aqueous lecithin dispersion and nanospheres (below 3%). Replacement of lecithin with polysorbate 80 in emulsions with polysorbate significantly increase (up to 8%) the fraction of benzalkonium chloride in the aqueous phase where microbial growth occurs.

Compatibility of Maximum Inorganic and Organic Calcium and Phosphate Content in Neonatal Parenteral Solutions.

The purpose of the study was to determine the maximum safe concentration of calcium and phosphate in neonatal parenteral nutrition (PN) solutions when various combinations of inorganic and organic salts are applied. Twelve PN solutions for neonatal use were aseptically prepared. Increasing concentrations of inorganic and organic calcium and phosphate were added to the standard formulas. Each admixture was separately tested according to the following conditions; after mixing, at 37 °C for 24 hr, and the maximum safe combination of calcium and phosphate were stored at 4 °C for 30 days and followed by 24 hr at 37 °C. Visual inspections and microscopic observation of undiluted PN solutions as well as the membrane filter after filtration of the PN solution, pH evaluation, and absorbance were examined. The safe maximum concentration of organic and inorganic calcium and phosphate were proposed individually for each composition of parenteral nutrition solutions. Surprisingly, organic calcium with organic phosphate showed precipitation but over the therapeutic range. The protective effect of amino acid was observed and higher concentrations of calcium and phosphate were free of precipitation. This work is valuable in daily practice as it allows an increase in the limits of calcium and phosphate in PN solutions for infants.

Evaluation of Y-site compatibility of home total parenteral nutrition and intravenous loop diuretics.

In chronic kidney disease (CKD), the design of the parenteral nutrition (PN) regimen becomes more challenging where only individualized PN is appropriate, coupled with the increased risk of unintended interactions with diuretic therapy. In an effort to ensure safe therapy in the home, we assessed the physical stability of bespoke PN formulations intended for use in CKD in the simultaneous presence of Y-site compatibility of furosemide and torasemide. The patient's daily needs were determined based on both metabolic demands as well as the demand for fluids.Complete admixtures were subjected to physical stability analysis consisting of visual inspection, a validated light microscope method, pH measurement, zeta potential measurement, and characterization of oily globule size distribution. Y-site compatibility of furosemide and torasemide with the formulated admixtures was also performed.The total parenteral admixture was stable over 7 days at +4°C and 24 h at +25°C and compatible via the Y-line together with furosemide and torasemide over 12 h at +25°C.The stability assessment guarantees the safety and efficiency of home PN with loop diuretics therapy in CKD patients. This means that these patients do not need long hospitalization and they can be safely treated at home. Furthermore, this study proved that torasemide is the same safety diuretic as furosemide, which has a great impact on clinical practice.

The effect of UV-protected ethylene vinyl acetate (EVA) bags on the physicochemical stability of pediatric parenteral nutrition admixtures.

BACKGROUND: The safe administration of parenteral admixtures should be considered under the headings of physical and chemical stability. Vitamins are considered to be most susceptible to chemical degradation. OBJECTIVES: To evaluate the protective effect of UV-protected monolayer ethylene vinyl acetate (EVA) bags in comparison with that of EVA bags without UV protection, on the physicochemical characteristics and stability of the light sensitive vitamins in pediatric parenteral admixtures stored under various temperature and light conditions. METHODS: Four different parenteral pediatric admixtures (with trace elements and vitamins) in two types of ethylenovinylacetate (EVA) monolayer containers (with - yellow one and without - transparent one UV protection) were assessed. The physicochemical analyses such as visual inspection, pH and potential zeta measurements, lipid globules size distribution and vitamins concentration were performed at 0 h, 24 h, 8 days and 8 days+24 h after the preparation of the TPN admixtures. In order to quantify ascorbic acid, thiamine and pyridoxine levels, HPLC was used. RESULTS: No differences (p < 0.05) in physicochemical stability of TPN admixtures were noted between two types of EVA bags, with the compositions assessed; stored 8 days (4 °C ± 2) without light plus 24 h at room temperature and light exposure. However significant differences were noticed in ascorbic acid, thiamine and pyridoxine content after 8 days+24 h in comparison with t = 0. This was noted for both for UV-protected bags and bags without UV-protection, Nevertheless, amounts were still within the pharmacopeial range. CONCLUSIONS: Both EVA bags under test (with and without UV-protection) ensure physicochemical stability up 8 days at 4 °C ± 2 °C without light exposure and then 24 h at room temperature with light exposure for the total pediatric parenteral admixtures, intended for home parenteral nutrition. Graphical abstract Scheme of physicochemical analysis of parenteral admixtures.

Stability of commercial parenteral lipid emulsions repacking to polypropylene syringes.

To accommodate small fluid volumes, repackaging of intravenous lipid emulsions is frequently performed in hospitals providing parenteral nutrition to neonates and smaller pediatric patients. The physical stability of lipid commercial parenteral emulsions repacked and stored in polypropylene syringe up to 30 days at room temperature, refrigerator and 40°C was determined to establish options for extended storage. Lipid emulsions in the manufacturers' original containers were used as references. Commercial lipid emulsions (20% of oil phase), ClinOleic, Intralipid, Smoflipid, Omegaven and Lipofindin LCT/MCT were repackaged under aseptic conditions in polypropylene syringes and stored at 4°C, 25°C and 40°C without light protection. Samples were assayed periodically over 30 days using validated, stability-indicating methods. Lipid emulsions in the manufacturers' containers stored in the same conditions were as references. Analysis of variance showed differences in the physical parameters due to temperature (p<0.05) and study day (p<0.05) but not the type of the emulsion (p = 0.98). The parenteral lipid emulsions in polypropylene syringe exhibited identical (except Z-avarage at 40°C, t = 30 days) to original containers time-dependent behavior taking into account the mean globule size, pH, and zeta potential measurements. Size of oily droplets of all test conditions remained below the United States Pharmacopeia limits. The results allow safe repacking of commercial lipid emulsion in a syringe, which is a necessary condition for supplying parenteral nutrition using the two-in-one method for newborns. However, longer storage than 12 h of repacked emulsion needs microbiological studies.

Comparison of the in vitro cytotoxicity among phospholipid-based parenteral drug delivery systems: Emulsions, liposomes and aqueous lecithin dispersions (WLDs).

Lecithin and isolated phospholipids (mainly phosphatidylcholine) have been used for years as pharmaceutical excipients in parenteral formulations: submicron emulsions, liposomes and mixed micelles. Under development are also other lecithin-based drug delivery systems, e.g. aqueous lecithin dispersions (WLDs). The aim of the study was to investigate the properties and potential cytotoxicity of 7 different phospholipid-based dispersions intended for parenteral administration: emulsions, liposomes and WLDs. Each formulation contained egg phosphatidylcholine (PC) in the concentration range of 0.6-5.0%, and to some formulations other surfactants, such as polysorbate 80 (P80), Solutol HS 15 (HS) and cholesterol (Ch) were added. Particles in all dispersions were homogenous (PDI < 0.26) and submicron in size (Z-average in the range of approx. 100-260 nm). The cytotoxicity of all tested formulations was evaluated by means of 3 independent methods: a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, a real-time xCELLigence (RTCA) system, and a flow cytometry analysis, using two cell lines: human embryonic kidney 293 (HEK-293) and human promyelocytic leukaemia (HL-60). The results indicated that regardless of the test method and cell line type, the cytotoxicity of all formulations was low, especially when dispersions diluted to concentrations of =10% were tested. A more pronounced cytotoxic effect was noticed only for the following formulations: E-P80 (emulsion containing P80), WLD (unbuffered aqueous lecithin dispersion) and L-Ch (liposomes containing Ch), tested as less diluted (concentration 10% or 25%). IC50 values measured for these dispersions (on HL-60 cells) amounted to: 10.4 ±â€¯0.5% (v/v), 14.4 ±â€¯0.2% (v/v) and 24.2 ±â€¯0.6% (v/v), respectively. Our investigation confirmed the biocompatibility of all tested phospholipid-based formulations: emulsions, liposomes and also newly-developed WLDs, which can be considered as safe parenteral drug carriers.

The presence of inorganic calcium in pediatric parenteral admixtures.

INTRODUCTION: Newborn infants and small children require large amounts of calcium and phosphate in a low volume of solution which can increase the risk of precipitation of calcium phosphate. Calcium gluconate is the predominant calcium salt form employed in parenteral nutrition (PN) compounding due to its solubility profile with phosphate. Unfortunately, calcium gluconate contains higher levels of aluminum contamination than calcium chloride, resulting in an increased potential for aluminum toxicity in patients receiving traditional PN. The physicochemical stability of 30 total parenteral admixtures containing inorganic calcium salts was evaluated. METHODS: Parenteral admixtures were prepared in one-chamber ethylene vinyl acetate bags: amino acids, glucose, electrolytes including only inorganic calcium salt and 20% (w/w) lipid emulsions (SMOFlipid®, Omegaven® or Lipofundin MCT/LCT®) were placed together in a one chamber bag. Admixtures were stored at +4 °C for up to eight days after preparation. Visual observations, globule size distribution (using optical microscopy, laser diffraction and photon correlation spectroscopy methods), pH analysis and zeta potential measurements were performed. RESULTS: The physicochemical stability of 29 of parenteral admixtures in the presence of inorganic calcium salt was confirmed. One admixture was deemed unsuitable for use in clinical practice due to the coalescence of oil droplets. CONCLUSION: Despite the presence of inorganic calcium salts, pediatric parenteral admixtures were stable up to eight days of storage. Due to presence of multiple components and a high risk of incompatibilities, physicochemical studies should be performed for each admixture before use in clinical practice.

INTRODUCCIÓN: los recién nacidos y los lactantes precisan aportes elevados de calcio y fósforo en soluciones con pequeño volumen lo que aumenta el riesgo de formar precipitados de fosfato cálcico. La principal sal de calcio empleado en nutrición parenteral (NP) es el gluconato cálcico, debido a su perfil de solubilidad con el fosfato. Lamentablemente el gluconato cálcico contiene unas concentraciones elevadas de aluminio mayores que el cloruro cálcico, lo que resulta en riesgo potencial de toxicidad por aluminio en pacientes que reciben NP. En este trabajo se evalúa la estabilidad fisicoquímica de 30 mezclas de NP con sales de calcio inorgánico. MÉTODOS: las mezclas de NP se prepararon en bolsas de acetato de etilenvinilo. En una bolsa unicameral se mezclaron aminoácidos, glucosa, y electrolitos incluyendo una sal de calcio inorgánico y una emulsión lipídica al 20% (SMOFlipid®, Omegaven®o Lipofundin MCT/LCT®). Las mezclas se almacenaron a +4 ° C hasta 8 días tras la elaboración. Se realizó un examen visual, estudio de la distribución del tamaño de los glóbulos (mediante microscopía óptica, difracción por láser y espectroscopia fotónica), análisis de pH y medición del potencial zeta. RESULTADOS: se confirmó la estabilidad fisicoquímica de 29 mezclas de NP que contenían sales de calcio inorgánico. Sólo una de las preparaciones se consideró inválida para su uso clínico debido a la coalescencia de las gotas de grasa. CONCLUSIÓN: a pesar de la presencia de sales de calcio inorgánico, las mezclas de NP pediátrica fueron estables hasta 8 días de almacenamiento. La presencia de múltiples componentes y el riesgo elevados de incompatibilidades hace recomendable el estudio de estabilidad fisicoquímica de cada mezcla antes de su empleo en la clínica.

The presence of inorganic calcium in pediatric parenteral admixtures / Presencia de calcio inorgánico en las soluciones pediátricas de nutrición parenteral

Introduction: Newborn infants and small children require large amounts of calcium and phosphate in a low volume of solution which can increase the risk of precipitation of calcium phosphate. Calcium gluconate is the predominant calcium salt form employed in parenteral nutrition (PN) compounding due to its solubility profile with phosphate. Unfortunately, calcium gluconate contains higher levels of aluminum contamination than calcium chloride, resulting in an increased potential for aluminum toxicity in patients receiving traditional PN. The physicochemical stability of 30 total parenteral admixtures containing inorganic calcium salts was evaluated. Methods: Parenteral admixtures were prepared in one-chamber ethylene vinyl acetate bags: amino acids, glucose, electrolytes including only inorganic calcium salt and 20% (w/w) lipid emulsions (SMOFlipid®, Omegaven® or Lipofundin MCT/LCT®) were placed together in a one chamber bag. Admixtures were stored at +4 °C for up to eight days after preparation. Visual observations, globule size distribution (using optical microscopy, laser diffraction and photon correlation spectroscopy methods), pH analysis and zeta potential measurements were performed. Results: The physicochemical stability of 29 of parenteral admixtures in the presence of inorganic calcium salt was confirmed. One admixture was deemed unsuitable for use in clinical practice due to the coalescence of oil droplets. Conclusion: Despite the presence of inorganic calcium salts, pediatric parenteral admixtures were stable up to eight days of storage. Due to presence of multiple components and a high risk of incompatibilities, physicochemical studies should be performed for each admixture before use in clinical practice (AU)

Introducción: los recién nacidos y los lactantes precisan aportes elevados de calcio y fosforo en soluciones con pequeño volumen lo que aumenta el riesgo de formar precipitados de fosfato cálcico. La principal sal de calcio empleado en nutrición parenteral (NP) es el gluconato cálcico, debido a su perfil de solubilidad con el fosfato. Lamentablemente el gluconato cálcico contiene unas concentraciones elevadas de aluminio mayores que el cloruro cálcico, lo que resulta en riesgo potencial de toxicidad por aluminio en pacientes que reciben NP. En este trabajo se evalúa la estabilidad fisicoquímica de 30 mezclas de NP con sales de calcio inorgánico. Métodos: las mezclas de NP se prepararon en bolsas de acetato de etilenvinilo. En una bolsa unicameral se mezclaron aminoacidos, glucosa, y electrolitos incluyendo una sal de calcio inorganico y una emulsión lipídica al 20% (SMOFlipidR, OmegavenR o Lipofundin MCT/LCTR). Las mezclas se almacenaron a +4 C hasta 8 días tras la elaboración. Se realizó un examen visual, estudio de la distribución del tamaño de los glóbulos (mediante microscopia óptica, difraccion por láser y espectroscopia fotonica), análisis de pH y medición del potencial zeta. Resultados: se confirmó la estabilidad fisicoquímica de 29 mezclas de NP que contenían sales de calcio inorgánico. Solo una de las preparaciones se consideró invalida para su uso clínico debido a la coalescencia de las gotas de grasa. Conclusión: a pesar de la presencia de sales de calcio inorgánico, las mezclas de NP pediátrica fueron estables hasta 8 días de almacenamiento. La presencia de múltiples componentes y el riesgo elevados de incompatibilidades hace recomendable el estudio de estabilidad fisicoquímica de cada mezcla antes de su empleo en la clínica (AU)

Formulation and characterization of EGCG for the treatment of superficial bladder cancer.

In the United States, the annual incidence of bladder cancer is approximately 70,000 new cases, with a mortality rate of approximately 15,000/year. The most common subtype (70%) of bladder cancer is superficial, namely hte non-muscle invasive disease form limited to the urothelium. The rate of progression and recurrence is up to 40 and 70%, respectively. Urothelial cell carcinoma of the bladder is typically treated with transurethral resection. The cancerous cells can float onto the adjacent epithelium, increasing the risk of recurrence. The standard of care is to offer adjuvant intravesical agents to reduce the risk of progression and recurrence. Current intravesical treatments are costly and are associated with special biohazard handling protocols. Patients are treated with intravesical therapy with bacillus Calmetter­Guerin (BCG) bacterium, or mitomycin C (MMC) following resection, both of which can cause moderate to severe side-effects which are rarely life-threatening. We previously examined the efficacy of epigallocatechin-3-gallate (EGCG) in comparison with MMC to prevent tumor cell implantation/growth in an animal model of superficial bladder cancer. Experiments revile that EGCG is slightly more effective than MMC at decreasing tumor cell implantation and consequent cancer growth in a bladder. This treatment requires the stringent sterile requirement of EGCG. EGCG can be unstable when sterilized at high temperatures. Thus, we evaluated two low temperature sterilization methods, such as ionizing radiation or the filtration method followed by freeze-drying. Both methods ensure the sterility of the sample; however, infrared and HPLC analysis revealed a slightly better stability of irradiated EGCG over the filtration method. The concentration of stable free radicals following irradiation was low, which are unlikely to exert any damaging effects to EGCG. Therefore, we consider that radiation will be the preferred method of EGCG sterilization, and that this may prove useful for the effective use of EGCG in the treatment of bladder cancer.

Determining whether curcumin degradation/condensation is actually bioactivation (Review).

Curcumin has been shown to exert therapeutic or protective effects against a variety of diseases, such as cancer, pulmonary diseases, neurological, liver, metabolic, autoimmune, cardiovascular diseases and numerous other chronic ailments. Over 116 clinical studies on curcumin in humans were registered with the US National Institutes of Health in 2015. However, it is mystifying how curcumin can be so effective in the treatment of many diseases since it has very low water solubility and bioavailability. Furthermore, curcumin is not stable under various conditions; its degradation or condensation into different bioactive compounds may be responsible for its biological activities rather than curcumin itself. In this review, we provide evidence of curcumin degradation and condensation into different compounds which have or may have health benefits themselves. Literature reviews strongly suggest that these molecules contribute to the observed health benefits, rather than curcumin itself.

Nutritional Support Teams: the cooperation among physicians and pharmacists helps improve cost-effectiveness of home parenteral nutrition (HPN) / Equipos de asistencia nutricional: la cooperación entre médicos y farmacéuticos ayuda a mejorar la rentabilidad de la nutrición parenteral domiciliaria (NPD)

Introduction: Modern home parenteral nutrition (HPN) requires the preparation of tailored admixtures. The physicians’ demands for their composition are often at the variance with pharmaceutical principles, which causes the necessity of either the preparation of ex tempore admixtures or stability testing ensuring long shelf life. Both approaches are not cost-effective. The aim of the study was to use the cooperation among physicians and pharmacists to assure both: cost-effectiveness and patient-tailored HPN admixtures. Methods: The first part of the study consisted of the thorough analysis of prescriptions for the most demanding 47 HPN patients (27 females and 20 males, mean age 53.1 year) treated at one HPN center to create few as possible long-shelf life admixtures. The second part of the study consisted of stability testing and modifications. Results: The analysis showed over 137 variations needed to cover all macro- and micronutrients requirements. Their cost as ex-tempore solutions was extremely high (over 110 000 EURO/month) due to logistics and similarly high if stability test for variation were to be performed (68 500 EURO). Therefore prescription was prepared de novo within team of physicians and pharmacists and four base models were designed. Water and electrolytes, particularly magnesium and calcium showed to be the major issues. Stability tests failed in one admixture due to high electrolytes concentration. It was corrected, and the new formula passes the test. Five basic models were then used for creation of new bags. Cost of such an activity were 3 700 EURO (p<0.01) Conclusions: The cooperation within the members of nutritional support team could improve the cost-effectiveness and quality of HPN (AU)

Introducción: La nutrición parenteral domiciliaria (NPD) moderna requiere la elaboración de preparados a medida. Las peticiones de los médicos en cuanto a la composición de estos preparados muchas veces difieren de los principios farmacéuticos, lo que suscita la necesidad de elaboración de preparados ex-tempore o unas pruebas de estabilidad que garanticen la almacenamiento a largo plazo. Estas estrategias no resultan rentables. El objetivo del estudio consistió en utilizar la cooperación entre médicos y farmacéuticos para asegurar tanto la rentabilidad, como la elaboración a medida de los preparados NPD. Métodos: La primera parte del estudio consistió en el análisis pormenorizado de las prescripciones para los 47 pacientes con una NPD más exigente (27 mujeres y 20 hombres, edad media 53,1 años) tratados en un centro NPD para crear el menor número posible de preparados de larga duración. La segunda parte del estudio consistió en pruebas de estabilidad y modificaciones. Resultados: El análisis demostró que eran necesarias más de 137 variaciones para cubrir todas las exigencias de macro y micronutrientes. Su costo como soluciones ex-tempore resultó extremadamente elevado (más de 110.000 EUROS/mes) debido a la logística, e igualmente alto en caso de requerirse una prueba de estabilidad (68.500 EUROS). Así, la prescripción fue preparada de novo por el equipo de médicos y farmacéuticos y se diseñaron cuatro modelos básicos. Las dificultades principales fueron el agua y los electrolitos, en particular magnesio y calcio. Las pruebas de estabilidad fracasaron en uno de los preparados debido a la alta concentración de electrolitos. Esto fue corregido, y la nueva fórmula supero la prueba. A partir de ahí se emplearon cinco modelos básicos para la creación de nuevas bolsas. El costo de esta actividad supuso 3.700 EUROS (p<0.01) Conclusiones: La cooperación entre los miembros del equipo de asistencia nutricional puede mejorar la rentabilidad y la calidad de la NPD (AU)

Finding new solutions in pediatric parenteral admixtures: how to improve quality and to deal with shortages.

INTRODUCTION: Pediatric parenteral nutrition enables normal growth even of preterm infants. Those children require, however, tailored parenteral nutrition and the creation of such can be challenging due to the risk of instability and shortages. OBJECTIVE: Prototypical parenteral admixtures were created using different calcium salts (organic and inorganic) and different lipid emulsions and tested for stability. 36 of parenteral admixtures containing two types of calcium salts: chloride or gluconolactobionate and different lipid emulsions (SMOFlipid® or Lipofundin MCT/LCT®) were under investigation. METHODS: Preliminary admixtures were prepared in two-chamber bags whereas lipid emulsions were placed separately in the second chamber. Pre-admixtures were stored for up to 21 days at +4ºC. Contents of the two chambers were combined at t = 0 or after 21 days of storage. Physical analysis of completed admixtures (visual inspection, microscopic observation, pH measurement and determination of the size distribution of oily droplets) was carried out after 21 days of the storage. Stability of lipid, commercial emulsions stored in ethylene vinyl acetate (EVA) bags for 42 days was also studied. RESULTS: Irrespectively of the time of storage of preadmixtures and type of calcium salt and different lipid emulsions among 36 total parenteral admixtures only one showed signs of destabilization after preparation and one was unstable when stored for longer than 14 days. All other formulations were qualified to be stable during the study. All investigated commercial lipid emulsions were physically stable in EVA bags even when stored at room temperature. CONCLUSION: The study proved that it was possible to store pre-admixture in EVA bags for 21 days at 4°C as well as that CAN (critical aggregation number) and CaxP (the products of multiplication of calcium and phosphate ions concentration) should not be used as reliable indicators of admixture physical stability. No influence of the type of calcium salts on stability of admixtures was observed.

INTRODUCCIÓN: La nutrición parenteral pediátrica permite un crecimiento normal incluso en lactantes pretérmino. Sin embargo, estos niños requieren una nutrición parenteral a medida y la formulación de tal nutrición puede suponer un reto por el riesgo de inestabilidad y el desabastecimiento. OBJETIVO: Se crearon mezclas parenterales prototípicas utilizando diferentes sales de calcio (orgánicas e inorgánicas) y diferentes emulsiones lipídicas probando su estabilidad. Se investigaron 36 mezclas parenterales que contenían dos tipos de sales de calcio (cloruro o gluconolactobionato) y diferentes emulsiones lipídicas (SMOFlipid® o Lipofundin MCT/LCT®). MÉTODOS: Se prepararon unas pre-mezclas en bolsas bicompartimentales mientras que las emulsiones lipídicas se colocaron de forma separada en la segunda cámara. Las pre-mezclas se almacenaron hasta 21 días a +4º C. Se combinaron los contenidos de ambas cámaras en t = 0 o después de 21 días de almacenamiento. El análisis físico de las mezclas completadas (inspección visual, observación microscópica, medición del pH y determinación de la distribución por tamaño de las gotitas lipídicas) se realizó a los 21 días de almacenamiento. También se estudió la estabilidad de las emulsiones lipídicas almacenadas en bolsas comerciales de acetato de etilen vinilo (AEV) durante 42 días. RESULTADOS: Independientemente del tiempo de almacenamiento de las pre-mezclas y el tipo de sal de calcio y de las diferentes emulsiones lipídicas de entre el total de 36 mezclas parenterales, sólo en una se vieron signos de desestabilización tras la preparación y una fue inestable cuando se almacenó más de 14 días. El resto de las formulaciones se consideraron estables durante el estudio. Todas las emulsiones lipídicas comerciales investigadas fueron estables físicamente en las bolsas de AEV, incluso cuando se almacenaron a temperatura ambiente. CONCLUSIÓN: El estudio mostró que es posible almacenar pre-mezclas en bolsas de AEV durante 21 días a 4° C. También se vio que el NAC (número de agregación crítica) y el CaxP (los productos de la multiplicación de las concentraciones de los iones calcio y fósforo) no deberían utilizarse como indicadores fiables de la estabilidad física de las mezclas. No se observó ninguna influencia del tipo de sal de calcio sobre la estabilidad de las mezclas.

Finding new solutions in pediatric parenteral admixtures; how to improve quality and to deal with shortages / Encontrando nuevas soluciones en las mezclas parenterales pediatricas; ¿cómo mejorar la calidad y gestionar el desabastecimiento?

Introduction: Pediatric parenteral nutrition enables normal growth even of preterm infants. Those children require, however, tailored parenteral nutrition and the creation of such can be challenging due to the risk of instability and shortages. Objective: Prototypical parenteral admixtures were created using different calcium salts (organic and inorganic) and different lipid emulsions and tested for stability. 36 of parenteral admixtures containing two types of calcium salts: chloride or gluconolactobionate and different lipid emulsions (SMOFlipid® or Lipofundin MCT/LCT®) were under investigation. Methods: Preliminary admixtures were prepared in two-chamber bags whereas lipid emulsions were placed separately in the second chamber. Pre-admixtures were stored for up to 21 days at +4ºC. Contents of the two chambers were combined at t = 0 or after 21 days of storage. Physical analysis of completed admixtures (visual inspection, microscopic observation, pH measurement and determination of the size distribution of oily droplets) was carried out after 21 days of the storage. Stability of lipid, commercial emulsions stored in ethylene vinyl acetate (EVA) bags for 42 days was also studied. Results: Irrespectively of the time of storage of preadmixtures and type of calcium salt and different lipid emulsions among 36 total parenteral admixtures only one showed signs of destabilization after preparation and one was unstable when stored for longer than 14 days. All other formulations were qualified to be stable during the study. All investigated commercial lipid emulsions were physically stable in EVA bags even when stored at room temperature. Conclusion: The study proved that it was possible to store pre-admixture in EVA bags for 21 days at 4°C as well as that CAN (critical aggregation number) and CaxP (the products of multiplication of calcium and phosphate ions concentration) should not be used as reliable indicators of admixture physical stability. No influence of the type of calcium salts on stability of admixtures was observed (AU)

Introducción: La nutrición parenteral pediátrica permite un crecimiento normal incluso en lactantes pretérmino. Sin embargo, estos niños requieren una nutrición parenteral a medida y la formulación de tal nutrición puede suponer un reto por el riesgo de inestabilidad y el desabastecimiento. Objetivo: Se crearon mezclas parenterales prototípicas utilizando diferentes sales de calcio (orgánicas e inorgánicas) y diferentes emulsiones lipídicas probando su estabilidad. Se investigaron 36 mezclas parenterales que contenían dos tipos de sales de calcio (cloruro o gluconolactobionato) y diferentes emulsiones lipídicas (SMOFlipid® o Lipofundin MCT/LCT®). Métodos: Se prepararon unas pre-mezclas en bolsas bicompartimentales mientras que las emulsiones lipídicas se colocaron de forma separada en la segunda cámara. Las pre-mezclas se almacenaron hasta 21 días a +4º C. Se combinaron los contenidos de ambas cámaras en t = 0 o después de 21 días de almacenamiento. El análisis físico de las mezclas completadas (inspección visual, observación microscópica, medición del pH y determinación de la distribución por tamaño de las gotitas lipídicas) se realizó a los 21 días de almacenamiento. También se estudió la estabilidad de las emulsiones lipídicas almacenadas en bolsas comerciales de acetato de etilen vinilo (AEV) durante 42 días. Resultados: Independientemente del tiempo de almacenamiento de las pre-mezclas y el tipo de sal de calcio y de las diferentes emulsiones lipídicas de entre el total de 36 mezclas parenterales, sólo en una se vieron signos de desestabilización tras la preparación y una fue inestable cuando se almacenó más de 14 días. El resto de las formulaciones se consideraron estables durante el estudio. Todas las emulsiones lipídicas comerciales investigadas fueron estables físicamente en las bolsas de AEV, incluso cuando se almacenaron a temperatura ambiente. Conclusión: El estudio mostró que es posible almacenar pre-mezclas en bolsas de AEV durante 21 días a 4° C. También se vio que el NAC (número de agregación crítica) y el CaxP (los productos de la multiplicación de las concentraciones de los iones calcio y fósforo) no deberían utilizarse como indicadores fiables de la estabilidad física de las mezclas. No se observó ninguna influencia del tipo de sal de calcio sobre la estabilidad de las mezclas (AU)

Evaluation of physical stability of all in one parenteral admixtures for pediatric home care with high electrolytes concentrations.

INTRODUCTION: The aim of the study was to evaluate stability of 48 total parenteral admixtures for pediatric patients who require home parenteral nutrition. Admixtures contain high amounts of electrolytes. In a clinical practice electrolytes-enrichment of the parenteral nutrition admixtures is a usual demand, especially on the neonatal/pediatric wards. The supplementation of parenteral nutrition with high concentration of electrolytes is a living problem due to decreased stability of lipid emulsions in nutrition admixtures caused by bivalent cations. METHODS: Preliminary admixtures were prepared in two-chamber ethylene vinyl acetate bags: amino acids, glucose and electrolytes were combined in one chamber and 20% (w/w) lipid emulsions (SMOFlipid®, Intralipid ® or ClinOleic®) were placed separately in the second chamber. Organic salts of calcium and phosphates were used. Pre-admixtures were stored at +4ºC for up to 21 days after preparation. Each composition of admixtures was prepared twice, because contents of the two chambers were combined at t=0 or after 21 days of storage at +4ºC. Visual observations, globule size distribution (using optical microscopy, laser diffraction and photon correlation spectroscopy methods), pH analyses, zeta potential and surface tension were performed after combining all components together with vitamins. RESULTS: Among 48 of investigated admixtures only two were problematic and other may be stored for at least 21 days at 4°C and completed admixtures demonstrated stability for at least 24 h at room temperature. CONCLUSION: It was possible to obtain stable admixtures despite of the high concentration of electrolytes.

Introducción: El objetivo del estudio fue evaluar la estabilidad de un total de 48 preparados o mezclas parenterales para pacientes pediátricos con necesidad de nutrición parenteral domiciliaria. Los preparados contienen cantidades elevadas de electrolitos. En la práctica clínica, el enriquecimiento con electrolitos de los preparados de nutrición parenteral es una demanda habitual, especialmente en las unidades neonatales/pediátricas. El complemento de la nutrición parenteral con altas concentraciones de electrolitos es un problema corrriente debido a la menor estabilidad de las emulsiones lipídicas en preparados de nutrición provocada por cationes bivalentes. Métodos: Se prepararon mezclas preliminares en bolsas de etilenvinilacetato de dos cámaras: se combinó amino ácidos, glucosa y electrolitos en una cámara y en la segunda cámara se puso por separado emulsiones lipídicas 20% (w/w) (SMOFlipid®, Intralipid® o ClinOleic®). Se utilizaron sales orgánicas de calcio y fosfatos. Se almacenaron pre-mezclas a +4ºC durante 21 días después de la preparación. Cada composición de mezcla fue preparada dos veces, dado que el contentido de las dos cámaras se combinó en t=0 o después de 21 días después del almacenamiento a +4ºC. Se realizaron observaciones visuales, distribución del tamaño globular (empleando métodos de microscopía óptica, difracción por láser y espectroscopía de correlación fotónica), análisis de pH, potencial zeta y tensión superficial después de combinar todos los componentes a la vez con vitaminas. Resultados: De los 48 preparados investigados solo dos resultaron problemáticos y el resto se pudo almacenar durante al menos 21 días a 4°C y las mezclas completadas presentaron estabilidad durante al menos 24 h a temperatura ambiente. Conclusión: Fue posible obtener preparados estables a pesar de la alta concentración de electrolitos.

Nutritional support teams: the cooperation among physicians and pharmacists helps improve cost-effectiveness of home parenteral nutrition (HPN).

INTRODUCTION: Modern home parenteral nutrition (HPN) requires the preparation of tailored admixtures. The physicians' demands for their composition are often at the variance with pharmaceutical principles, which causes the necessity of either the preparation of ex tempore admixtures or stability testing ensuring long shelf life. Both approaches are not cost-effective. The aim of the study was to use the cooperation among physicians and pharmacists to assure both: cost-effectiveness and patient-tailored HPN admixtures. METHODS: The first part of the study consisted of the thorough analysis of prescriptions for the most demanding 47 HPN patients (27 females and 20 males, mean age 53.1 year) treated at one HPN center to create few as possible long-shelf life admixtures. The second part of the study consisted of stability testing and modifications. RESULTS: The analysis showed over 137 variations needed to cover all macro- and micronutrients requirements. Their cost as ex-tempore solutions was extremely high (over 110 000 EURO/month) due to logistics and similarly high if stability test for variation were to be performed (68 500 EURO). Therefore prescription was prepared de novo within team of physicians and pharmacists and four base models were designed. Water and electrolytes, particularly magnesium and calcium showed to be the major issues. Stability tests failed in one admixture due to high electrolytes concentration. It was corrected, and the new formula passes the test. Five basic models were then used for creation of new bags. Cost of such an activity were 3 700 EURO (p<0.01) CONCLUSIONS: The cooperation within the members of nutritional support team could improve the cost-effectiveness and quality of HPN.

Introducción: La nutrición parenteral domiciliaria (NPD) moderna requiere la elaboración de preparados a medida. Las peticiones de los médicos en cuanto a la composición de estos preparados muchas veces difieren de los principios farmacéuticos, lo que suscita la necesidad de elaboración de preparados ex-tempore o unas pruebas de estabilidad que garanticen la almacenamiento a largo plazo. Estas estrategias no resultan rentables. El objetivo del estudio consistió en utilizar la cooperación entre médicos y farmacéuticos para asegurar tanto la rentabilidad, como la elaboración a medida de los preparados NPD. Métodos: La primera parte del estudio consistió en el análisis pormenorizado de las prescripciones para los 47 pacientes con una NPD más exigente (27 mujeres y 20 hombres, edad media 53,1 años) tratados en un centro NPD para crear el menor número posible de preparados de larga duración. La segunda parte del estudio consistió en pruebas de estabilidad y modificaciones. Resultados: El análisis demostró que eran necesarias más de 137 variaciones para cubrir todas las exigencias de macro y micronutrientes. Su costo como soluciones ex-tempore resultó extremadamente elevado (más de 110.000 EUROS/mes) debido a la logística, e igualmente alto en caso de requerirse una prueba de estabilidad (68.500 EUROS). Así, la prescripción fue preparada de novo por el equipo de médicos y farmacéuticos y se diseñaron cuatro modelos básicos. Las dificultades principales fueron el agua y los electrolitos, en particular magnesio y calcio. Las pruebas de estabilidad fracasaron en uno de los preparados debido a la alta concentración de electrolitos. Esto fue corregido, y la nueva fórmula supero la prueba. A partir de ahí se emplearon cinco modelos básicos para la creación de nuevas bolsas. El costo de esta actividad supuso 3.700 EUROS (p.

Antimicrobial activity of parabens in submicron emulsions stabilized with lecithin.

Antimicrobial efficacy of methyl and propylparaben combination as potential preservatives for submicron emulsions, and the effect of oil and lecithin concentration on the microbial growth were investigated. Parabens were ineffective in standard or doubled concentrations as per pharmacopoeial criteria. Poor growth inhibition and multiplication of reference strains point to protective and growth properties of submicron emulsions. No correlation was observed between oil/lecithin ratio and efficacy of parabens; partitioning of the latter into the oily phase and lipophilic domains could be the reason for such effect. Further studies are necessary to establish a stable and safe composition of such formulations.

Partitioning of parabens between phases of submicron emulsions stabilized with egg lecithin.

Partitioning of methyl and propyl parabens (methyl and propyl hydroxybenzoate, paraben M and P) between the major phases in the parenteral submicron emulsions was studied. The investigated emulsions contained 10% or 20% soya-bean oil, 1.2% or 2.4% egg lecithin, 0.18% or 0.36% paraben M and 0.02% or 0.04% paraben P. The aqueous phase was obtained by ultracentrifugation, and subsequently, it was subjected to ultrafiltration, which procedure allowed to distinguish between the fractions of free preservatives (Fw) and incorporated in the liposomal or micellar region (Flm). The fractions present in the oily phase and in the interface were calculated. Depending on the formulation, Fw was 17-31% and 2.3-6.0% for paraben M and P, respectively. The Flm values were in a very narrow range, i.e. 3.0-6.0% for both preservatives. Substantial accumulation, i.e. 38-58% was found in the interface and the partitioning into this region was related to the oil/lecithin ratio rather than to lipophilicity of the preservative.