ABSTRACT
The ESPGHAN/ESPEN/ESPR-Guidelines on pediatric parenteral nutrition (PPN) recommend the administration of the semiessential amino acid (AA) cysteine to preterm neonates due to their biochemical immaturity resulting in an inability to sufficiently synthetize endogenous cysteine. The soluble precursor N-acetylcysteine (NAC) is easily converted into bioavailable cysteine. Its dimer N,N-diacetylcystine (DAC) is almost unconvertable to cysteine when given intravenously resulting in a diminished bioavailability of cysteine. This study aims to understand the triggers and oxidation process of NAC to DAC to evaluate possibilities of reducing DAC formation in standardized PPN. Therefore, different air volumes (21% O2) were injected into the AA compartment of a standardized dual-chamber PPN. O2 concentrations were measured in the AA solution and the headspaces of the primary and secondary packaging. NAC and DAC concentrations were analyzed simultaneously. The analysis showed that O2 is principally delivered from the primary headspace. NAC oxidation exclusively delivers DAC, depending on the O2 amount in the solution and the headspaces. The reaction of NAC to DAC being containable by limiting the O2 concentration, the primary headspace must be minimized during manufacturing, and oxygen absorbers must be added into the secondary packaging for a long-term storage of semipermeable containers.
Subject(s)
Acetylcysteine/administration & dosage , Amino Acids/administration & dosage , Cystine/analogs & derivatives , Drug Stability , Infant, Premature , Parenteral Nutrition Solutions/chemistry , Parenteral Nutrition , Acetylcysteine/metabolism , Amino Acids/metabolism , Biological Availability , Cysteine/administration & dosage , Cysteine/metabolism , Cystine/metabolism , Drug Industry , Drug Storage , Humans , Infant Nutritional Physiological Phenomena , Infant, Newborn , Nutritional Requirements , Oxidation-Reduction , OxygenABSTRACT
Drug solubility testing in biorelevant media has become an indispensable tool in pharmaceutical development. Despite this importance, there is still an incomplete understanding of how poorly soluble compounds interact with these media. The aim of this study was to apply the concept of the apparent solubilization capacity to fasted and fed state simulated intestinal fluid (FaSSIF and FeSSIF, respectively). A set of non-ionized poorly soluble compounds was studied in biorelevant media prepared from an instantly dissolving complex (SIF(™) Powder) at 37°C. The values of the solubilization capacity were different between FaSSIF and FeSSIF but correlated. Drug inclusion into the mixed micelles was highly specific for a given compound. The ratio of the FeSSIF to FaSSIF solubility was in particular considered and discussed in terms of the apparent solubilizing capacity. The apparent solubilization concept appears to be useful for the interpretation of biorelevant solubility tests. Further studies are needed to explore acidic and basic drugs.
Subject(s)
Gastrointestinal Contents/chemistry , Pharmaceutical Preparations/chemistry , Water/chemistry , Biological Availability , Fasting , Humans , Micelles , Models, Molecular , Nutritional Status , Particle Size , Pharmacokinetics , SolubilityABSTRACT
The features of a new, in situ method for solubilizing poorly soluble drugs (SupraVail Instant Solubilization) are demonstrated. The resulting formulations are suitable for parenteral administration in preclinical and clinical studies. The technique avoids drug precipitation upon dilution and circumvents the need for co-administration of high organic solvent concentrations. The method involves mixing a sterile solution of a poorly water-soluble drug in a water-miscible organic solvent (the "transfer medium") with an excess of a sterile, stable, phospholipid dispersion prepared by high-shear homogenization. The influence of several mixing parameters which may affect the utility and viability of the method for two drugs, namely diazepam or cyclosporine A, are examined in detail. The resulting transparent dispersions were analyzed for presence of insoluble particles, transmission, particle size, and degree of solubilization. It is found that solubilizing efficiency is mainly determined by the drug and the phospholipid-to-drug ratio in the final dispersion. Complete and instant solubilization is obtained by using negatively charged phospholipids in the transfer medium. Variations in the mixing conditions, such as fast addition compared to slow addition, no shaking (agitation) versus shaking during mixing, stirring after mixing, and temperature variations of the lipid dispersion do not significantly affect the reproducibility of the method.
Subject(s)
Pharmaceutical Preparations/chemistry , Phospholipids/chemistry , Cyclosporine/chemistry , Diazepam/chemistry , Infusions, Parenteral , Particle Size , SolubilityABSTRACT
A new and particularly mild method for the formation of phosphorus-sulfur bonds has been achieved through base-catalyzed addition of thiocyanate to the corresponding H-phosphine oxide, phosphinate, or phosphonate. This reaction procedure offers many advantages: the use as starting material of a stable and not oxygen-sensitive phosphorus(v) species, particularly mild and nonaqueous reaction conditions and workup (a pivotal point for these sensitive phosphonothioates), and, through optimized access to thiocyanates, a wider scope of substrates. This method has been applied to achieve the synthesis of substrate analogues for the study of antibody-catalyzed hydrolysis of acetylcholinesterase inhibitor PhX (11).
