The impact of first-aid dressing design on healing of porcine partial thickness wounds.

Literature describes that a well-maintained moist wound healing environment leads to faster healing by preventing scabbing and drying of the wound. A moist wound speeds healing by allowing for unimpeded movement of newly dividing epidermal cells in the wound. Contrary to what is described in literature and practiced by clinicians, first-aid dressings used at home by consumers advertise breathability and absorptivity as benefits. This manuscript examines the effects of dressing breathability and highly absorptive pads on healing and wound appearance in a porcine dermatome wound model, designed to mimic an abrasion injury. Partial thickness wounds were covered with an experimental silicone-polymer film dressing and various over-the-counter bandages for time frames ranging from 4 to 11 days. The progression of healing was quantified by histology and wound-size reduction measurements. The thickness and persistence of a scab or serocellular crust (SCC) over the injury was measured using both pixel density and optical coherence tomography to supplement visual observations, demonstrating new tools for quantification of SCC over wounds. The results of the experiments illustrate the impact of dressing features on the rate of wound reepithelialization and the formation of SCC. Both a low moisture vapor transmission rate (MVTR) and the absence of an absorptive layer were important in speeding wound healing. Surprisingly, use of a dressing with a low MVTR and a highly absorptive pad healed significantly more slowly than a comparative dressing with a low MVTR and no absorptive pad, even though both dressings had very little scab formation over the wound. This study shows that breathability and absorbency of dressings play independent roles in providing an optimal healing environment, and that these properties can vary widely among commercially available dressings.

Interplay of degradation, dissolution and stabilization of clarithromycin and its amorphous solid dispersions.

Clarithromycin (CLA) is an aminomacrolide antibiotic whose physical properties are fascinating and challenging. It has very poor solubility at neutral intestinal pH, but much better solubility under acidic conditions due to amine protonation. The improved solubility in an acid environment is confounded by the poor chemical stability of clarithromycin that is quite labile toward acid-catalyzed degradation. This creates a complex system under gastrointestinal (GI) conditions: dissolution in the stomach, degradation, potential for precipitation in the small intestine, and interplay with the formulation components. We report herein a study of amorphous solid dispersion (ASD) of CLA with carboxyl-containing cellulose derivatives, which have recently been shown to be excellent ASD matrices for maximizing oral bioavailability. This approach was intended to improve CLA solubility in neutral media while minimizing release in an acid environment, and thereby increase its uptake from the small intestine. Amorphous polymer/CLA nanoparticles were also prepared by high-shear mixing in a multi-inlet vortex mixer (MIVM). Different extents of release were observed at low pH from the various formulations. Thus the solubility increase from nanosizing was deleterious to the concentration of intact CLA obtained upon reaching small intestine conditions; the high extent of release at gastric pH led to complete degradation of CLA. Using pH-switch experiments, it was possible to separate the effects of loss of CLA from solution by crystallization vs. that from chemical degradation. It was found that the hydrophobic cellulose derivative cellulose acetate adipate propionate (CAAdP) was effective at protecting CLA from dissolution in the stomach, and preventing CLA decomposition at low pH; 54% of CLA in CAADP ASD was released intact, vs. 0% and 6% from HPMCAS and CMCAB ASDs, respectively. We conclude that protection against degradation is central to enhancing overall release of intact CLA from ASD formulations; the formulations studied herein have great promise for simultaneous CLA solubility enhancement and protection from loss to chemical degradation, thereby reducing dose requirements and potentially decreasing colonic exposure to CLA (reduced colonic exposure is expected to minimize killing of beneficial colonic bacteria by CLA).

Anacardic acid derivatives as inhibitors of glyceraldehyde-3-phosphate dehydrogenase from Trypanosoma cruzi.

Chagas' disease, a parasitic infection caused by the flagellate protozoan Trypanosoma cruzi, is a major public health problem affecting millions of individuals in Latin America. On the basis of the essential role in the life cycle of T. cruzi, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been considered an attractive target for the development of novel antitrypanosomatid agents. In the present work, we describe the inhibitory effects of a small library of natural and synthetic anacardic acid derivatives against the target enzyme. The most potent inhibitors, 6-n-pentadecyl- and 6-n-dodecylsalicilic acids, have IC(50) values of 28 and 55 microM, respectively. The inhibition was not reversed or prevented by the addition of Triton X-100, indicating that aggregate-based inhibition did not occur. In addition, detailed mechanistic characterization of the effects of these compounds on the T. cruzi GAPDH-catalyzed reaction showed clear noncompetitive inhibition with respect to both substrate and cofactor.

Rifampin Stability and Solution Concentration Enhancement Through Amorphous Solid Dispersion in Cellulose ω-Carboxyalkanoate Matrices.

Tuberculosis (TB) is a deadly infectious disease; approximately 2 billion people are currently latently infected with the causative agent Mycobacterium tuberculosis. Approximately 8 million new active cases and 2 million deaths due to TB are recorded annually.1 Rifampin (Rif) is a vital first-line TB treatment drug. Its effectiveness is hampered by the high dose required (600 mg 1×/day) and by its moderate, variable bioavailability. These issues can be explained by Rif instability at gastric pH, limited solubility at neutral pH, polymorphism, and stimulation of its own metabolism. To overcome these obstacles, we developed new cellulose-based oral drug delivery systems aiming to increase and make more consistent Rif solubility and bioavailability. Amorphous solid dispersions (ASDs) of Rif with cellulose ω-carboxyalkanoates (cellulose acetate suberate, cellulose acetate propionate adipate, and cellulose acetate butyrate sebacate) were prepared and compared with crystalline Rif (negative) and carboxymethyl cellulose acetate butyrate ASD (positive) controls. Cellulose ω-carboxyalkanoate ASDs prevented acid-catalyzed degradation in conditions mimicking the acidic stomach and provided complete release of intact Rif at intestinal pH. Rif incorporation into ASD in these novel cellulose derivative matrices creates the potential for convenient, robust, consistent, and high Rif oral bioavailability for treatment of TB.

Synthesis of amphiphilic 6-carboxypullulan ethers.

Hydrophobically modified polysaccharides that contain carboxyl groups possess exceptional features for drug delivery and other applications. Carboxyl groups were introduced at C-6 in the pullulan backbone by applying the well-established oxidation with TEMPO and NaOCl/NaBr. The oxidized product, 6-carboxypullulan, is even more water-soluble than pullulan. Consequently, further chemical modifications have been mainly restricted to reactions that can be performed in water or under heterogeneous conditions. We find that the TBA salt of 6-carboxypullulan is soluble in a range of organic solvents and can be reacted homogeneously with various alkyl halides in DMSO and sodium hydroxide at 40 °C to yield 6-carboxypullulan ethers. Complete substitution (DS 7 per trisaccharide repeat unit) was achieved upon reaction with iodoethane, while products from reaction with longer chain alkyl halides (propyl and butyl derivatives) achieved DS up to about 3. The amphiphilic products have impressive surfactant properties.