Temperature stability of oxytocin ampoules labelled for storage at 2°C-8°C and below 25°C: an observational assessment under controlled accelerated and temperature cycling conditions.

Introduction: Oxytocin, administered via injection, is recommended by WHO for the prevention and treatment of postpartum haemorrhage. However, the susceptibility of oxytocin injection to thermal degradation has led WHO and UNICEF to recommend cold-chain storage of all oxytocin products. Nevertheless, some oxytocin products supplied to the global market are labelled for storage at ≤25°C, often with a shorter shelf-life relative to products labelled for refrigeration.

Precise control of drug loading and release of an NSAID-polymer conjugate for long term osteoarthritis intra-articular drug delivery.

A facile synthesis method of polymer diclofenac conjugates (PDCs) based on biocompatible polyurethane chemistry that provides a high drug loading and offers a high degree of control over diclofenac (DCF) release kinetics is described. DCF incorporating monomer was reacted with ethyl-l-lysine diisocyanate (ELDI) and different amounts of polyethylene glycol (PEG) in a one-step synthesis to yield polymers with pendent diclofenac distributed along the backbone. By adjusting the co-monomers feed ratio, the drug loading could be tailored accordingly to give DCF loading of up to 38 w/w%.

The Hydrolysis of Diclofenac Esters: Synthetic Prodrug Building Blocks for Biodegradable Drug-Polymer Conjugates.

Degradation reactions on diclofenac-monoglycerides (3a,b), diclofenac-(p-hydroxybenzoate)-2-monoglyceride (3c), diclofenac (1), and diclofenac lactam (4) were performed at 37 °C in isotonic buffer solutions (apparent pH range 1-8) containing varying concentrations of acetonitrile (ACN). The concentration remaining of each analyte was measured versus time. Diclofenac-monoglycerides and diclofenac-(p-hydroxybenzoate)-2-monoglyceride (3c) were both found to undergo facile and complete hydrolysis in pH 7.

The physicochemical properties of geraniin, a potential antihyperglycemic agent.

Context: Natural products play a vital role in the discovery of leads for novel pharmacologically active drugs. Geraniin (GE) was identified as the major compound in the rind of Nephelium lappaceum L. (Sapindaceae), while ellagic and gallic acids have been shown to be its main metabolites.

Interaction of model aryl- and alkyl-boronic acids and 1,2-diols in aqueous solution.

The goal of this work was to quantitate ester formation between alkyl and aryl boronic acids and vicinal-diols or 1,2-diols in aqueous solution. As used here, 1,2-diols includes polyols with one or more 1,2-diol pairs. Multiple techniques were used including apparent pKa shifts of the boronic acids using UV spectrophotometry (for aryl acids) and titration (for aryl and alkyl acids).

Evaluation of the impact of sulfobutylether7 -β-cyclodextrin on the liquid chromatography-mass spectrometry analysis of biological samples arising from in vivo pharmacokinetic studies.

The utility of cyclodextrin (CD) complexation in improving apparent solubility of drugs in parenteral formulations is well established. Administration of these formulations delivers CD directly into the systemic circulation, and it may be necessary to demonstrate unaltered in vivo disposition of a drug coadministered with a CD. Crucial to the undertaking of such a study is the need for bioanalytical assays in which CD presence does not impact drug quantitation.

The effect of intravenous sulfobutylether7 -β-cyclodextrin on the pharmacokinetics of a series of adamantane-containing compounds.

Intravenously administered (i.v.) drug-cyclodextrin (CD) inclusion complexes are generally expected to dissociate rapidly and completely, such that the i.

Pulmonary delivery of an ultra-fine oxytocin dry powder formulation: potential for treatment of postpartum haemorrhage in developing countries.

Oxytocin is recommended by the World Health Organisation as the most effective uterotonic for the prevention and treatment of postpartum haemorrhage. The requirement for parenteral administration by trained healthcare providers and the need for the drug solution to be maintained under cold-chain storage limit the use of oxytocin in the developing world. In this study, a spray-dried ultrafine formulation of oxytocin was developed with an optimal particle size diameter (1-5 µm) to facilitate aerosolised delivery via the lungs.

The Acid/Base Profile of the Human Metabolome and Natural Products.

Human small molecule metabolites (the human metabolome) are a set of compounds that interact with at least one macromolecule in the biosphere. This study investigates the acid/base profile of the human metabolome, natural products and drugs, together with an analysis of their physicochemical properties. Ionisation constants (pKa values) are estimated for each compound and the identity of the ionisable functional groups in each set is determined.

A chemogenomic analysis of ionization constants--implications for drug discovery.

Chemogenomics methods seek to characterize the interaction between drugs and biological systems and are an important guide for the selection of screening compounds. The acid/base character of drugs has a profound influence on their affinity for the receptor, on their absorption, distribution, metabolism, excretion and toxicity (ADMET) profile and the way the drug can be formulated. In particular, the charge state of a molecule greatly influences its lipophilicity and biopharmaceutical characteristics.

The significance of acid/base properties in drug discovery.

While drug discovery scientists take heed of various guidelines concerning drug-like character, the influence of acid/base properties often remains under-scrutinised. Ionisation constants (pK(a) values) are fundamental to the variability of the biopharmaceutical characteristics of drugs and to underlying parameters such as logD and solubility. pK(a) values affect physicochemical properties such as aqueous solubility, which in turn influences drug formulation approaches.

Interaction of colistin and colistin methanesulfonate with liposomes: colloidal aspects and implications for formulation.

Interaction of colistin and colistin methanesulfonate (CMS) with liposomes has been studied with the view to understanding the limitations to the use of liposomes as a more effective delivery system for pulmonary inhalation of this important class of antibiotic. Thus, in this study, liposomes containing colistin or CMS were prepared and characterized with respect to colloidal behavior and drug encapsulation and release. Association of anionic CMS with liposomes induced negative charge on the particles.

Stability and sterility of diluted enoxaparin under three different storage conditions.

Aim: This study assessed whether enoxaparin sodium diluted to a concentration of 20 mg/mL for clinical use with 0.9% sodium chloride remained stable and sterile for up to 43 days under three different storage conditions.

Methods: Enoxaparin dilutions in polypropylene syringes were stored under three different controlled conditions of temperature and light: (i) room temperature (22-26°C) under natural light; (ii) room temperature (22-26°C) in the dark; and (iii) controlled refrigeration (2-8°C) in the dark.

Self-assembly behavior of colistin and its prodrug colistin methanesulfonate: implications for solution stability and solubilization.

Colistin is an amphiphilic antibiotic that has re-emerged into clinical use due to the increasing prevalence of difficult-to-treat Gram-negative infections. The existence of self-assembling colloids in solutions of colistin and its derivative prodrug, colistin methanesulfonate (CMS), was investigated. Colistin and CMS reduced the air-water interfacial tension, and dynamic light scattering (DLS) studies showed the existence of 2.

Impact of chlorpromazine self-association on its apparent binding constants with cyclodextrins: Effect of SBE(7)-beta-CD on the disposition of chlorpromazine in the rat.

Chlorpromazine is an antipsychotic agent with poor aqueous solubility. Complexation with SBE(7)-beta-CD can aid intravenous delivery through increasing the apparent solubility of chlorpromazine. However, chlorpromazine has also been known to self-associate.

Stability of peroxide antimalarials in the presence of human hemoglobin.

Peroxide antimalarials, including artemisinin, are important for the treatment of multidrug-resistant malaria. These peroxides are known to react with iron or heme to produce reactive intermediates that are thought to be responsible for their antimalarial activities. This study investigated the potential interaction of selected peroxide antimalarials with oxyhemoglobin, the most abundant form of iron in the human body.

A protocol for the combined sub-fractionation and delipidation of lipid binding proteins using hydrophobic interaction chromatography.

Cellular lipids frequently co-purify with lipid binding proteins isolated from tissue extracts or heterologous host systems and as such hinder in vitro ligand binding approaches for which the apo-protein is a prerequisite. Here we present a technique for the complete removal of unesterified fatty acids, phospholipids, steroids and other lipophilic ligands bound to soluble proteins, without protein denaturation. Peroxisome proliferator activated receptor gamma ligand binding domain and intracellular fatty acid binding proteins were expressed in an Escherichia coli host and completely delipidated by hydrophobic interaction chromatography using phenyl sepharose.

Preparation and in vitro evaluation of novel lipopeptide transfection agents for efficient gene delivery.

Gene therapy by delivery of nonviral expression vectors is highly desirable, due to their safety, stability, and suitability for production as bulk pharmaceuticals. However, low transfection efficiency remains a limiting factor in application on nonviral gene delivery. Despite recent advances in the field, there are still major obstacles to overcome.

Relationship between antimalarial activity and heme alkylation for spiro- and dispiro-1,2,4-trioxolane antimalarials.

The reaction of spiro- and dispiro-1,2,4-trioxolane antimalarials with heme has been investigated to provide further insight into the mechanism of action for this important class of antimalarials. A series of trioxolanes with various antimalarial potencies was found to be unreactive in the presence of Fe(III) hemin, but all were rapidly degraded by reduced Fe(II) heme. The major reaction product from the heme-mediated degradation of biologically active trioxolanes was an alkylated heme adduct resulting from addition of a radical intermediate.

Probing the flexibility of the DsbA oxidoreductase from Vibrio cholerae--a 15N - 1H heteronuclear NMR relaxation analysis of oxidized and reduced forms of DsbA.

We have determined the structure of the reduced form of the DsbA oxidoreductase from Vibrio cholerae. The reduced structure shows a high level of similarity to the crystal structure of the oxidized form and is typical of this class of enzyme containing a thioredoxin domain with an inserted alpha-helical domain. Proteolytic and thermal stability measurements show that the reduced form of DsbA is considerably more stable than the oxidized form.

Iron-mediated degradation kinetics of substituted dispiro-1,2,4-trioxolane antimalarials.

The iron-mediated reactivity of various dispiro-1,2,4-trioxolanes was determined by automated kinetic analysis under standard reaction conditions. The active antimalarial compounds underwent peroxide bond cleavage by Fe(II) resulting in products indicative of carbon-centered radical formation. The rate of reaction was heavily influenced by the presence of spiro-substituted adamantane and cyclohexane rings, and was also significantly affected by cyclohexane ring substitution.