Fluocinolone Acetonide Microemulsion in Combination with a Fractional Laser for the Treatment of Scalp Psoriasis.

This study introduces fluocinolone acetonide (FA) microemulsion in combination with ablative fractional lasering as a new effective treatment for scalp psoriasis. A pseudo-ternary phase diagram was constructed using the aqueous titration method. The suitable ratio of surfactant mixture (Smix):oil mixture (Omix):water was chosen from the microemulsion region of the diagram. FA was loaded into the selected ratio to prepare FA microemulsion. Ex vivo skin permeation study of the FA microemulsion with fractional laser assistance was performed to determine a proper ablative depth. A pilot clinical study was conducted to evaluate the efficacy of FA microemulsion and FA microemulsion combination with lasering at the optimum ablation depth. The selected microemulsion base contained (in wt%) 77% water, 20% Smix (Tween 80:ethanol, 2:1), 3% Omix (10% benzyl benzoate and 1% benzyl alcohol in bergamot oil), and 0.2% sodium carboxymethylcellulose. FA was loaded into this base at a concentration of 0.1%. The skin lasered at an ablation depth of 50 µm was conducted in the pilot clinical study. Scalp psoriasis responded well to the FA microemulsion. Psoriasis scalp severity index (PSSI) scores indicated that the FA microemulsion plus laser treatment provides higher efficacy than the FA microemulsion alone without any topical and systemic side effects. The efficacy of the treatments could be maintained for at least 1 week after treatment discontinuation. FA microemulsion was properly formulated and evaluated. The microemulsion demonstrating the greatest benefits was used in combination with ablative fractional lasering to treat scalp psoriasis.

The interaction mechanism between lipopeptide (daptomycin) and polyamidoamine (PAMAM) dendrimers.

The interaction mechanism of lipopeptide antibiotic daptomycin and polyamidoamine (PAMAM) dendrimers was studied using fluorescence spectroscopy. The fluorescence changes observed are associated with daptomycin-dendrimer interactions. The binding isotherms were constructed by plotting the fluorescence difference at 460 nm from kynurenine (Kyn-13) of daptomycin in the presence and absence of dendrimer. A one-site and two-site binding model were quantitatively generated to estimate binding capacity and affinity constants from the isotherms. The shape of the binding isotherm and the dependence of the estimated capacity constants on dendrimer sizes and solvent pH values provide meaningful insight into the mechanism of interactions. A one-site binding model adequately describes the binding isotherm obtained under a variety of experimental conditions with dendrimers of various sizes in the optimal binding pH region 3.5 to 4.5. Comparing the pH-dependent binding capacity with the ionization profiles of daptomycin and dendrimer, the ionized aspartic acid residue (Asp-9) of daptomycin primarily interact with PAMAM cationic surface amine.

An evaluation of a fluorometric method for determining binding parameters of drug-carrier complexes using mathematical models based on total drug concentration.

A fluorescence method for determining the mode of binding and estimating binding parameters in a model drug-carrier complex was developed using the lipopeptide antibiotic daptomycin and polyamidoamine (PAMAM) dendrimer. Mathematical simulations of model equations describing fluorescence changes induced by antibiotic-carrier binding in terms of total drug concentration were used to evaluate the sensitivity of parameter variation on binding isotherms for both one- and two-site binding models. Nonlinear regression analysis was used to estimate binding parameters and to identify pH-dependent binding models.

HPMC effect on catalyzed hydrolysis of alpha-naphthyl acetate in cationic micellar systems.

Micelle formation is an important property of surfactants. Micellar solutions of cetyltrimethylamonium bromide (CTAB) have been found to accelerate the hydrolysis of alpha-naphthyl acetate (alpha-NA) by o-iodosobenzoic acid (IBA), a strong nucleophile. Critical micelle concentration (CMC) of CTAB was determined in the absence and presence of various concentrations and grades of hydroxypropylmethyl cellulose (HPMC) using surface tension measurement. Reaction under pseudo-first-order condition was utilized for rate constant determination. The aggregation of CTAB in the polymer solution started at higher concentration than in the absence of the polymer. The observed rate constants for the degradation of alpha-NA in the presence of various concentrations of CTAB with and without HPMC were calculated. The presence of HPMC retarded the reaction rate. However, there was no obvious difference in the observed rate constant among the different grades of HPMC (Methocel E50, Methocel E4M, Methocel E10M) while the higher the polymer concentration the lower the rate constant.

The protein-binding and drug release properties of macromolecular conjugates containing daptomycin and dextran.

Prototype daptomycin-dextran macromolecular conjugates were prepared in an attempt to modify the biodistribution and protein-binding properties of daptomycin. Synthesis of daptomycin macromolecular conjugates involved dextran activation, daptomycin-dextran coupling, and purification. The reaction mixtures were separated on a Sephadex G-100 column using 10% acetronitrile in water as a mobile phase. UV and fluorescence characteristics of high molecular weight fractions demonstrated imine product formation while the lower molecular weight fractions contained free daptomycin, imine, and anilide products. Daptomycin macromolecular conjugates were characterized by drug loading, drug release, and binding affinity for fibrinogen using HPLC analysis and surface plasmon resonance. Drug loading was calculated to be 160mg of daptomycin per gram of macromolecule. Approximately 9% of the conjugated daptomycin was released from the macromolecular conjugates in aqueous media in the pH range of 1-7.4. The conjugates possessed higher affinity for fibrinogen than that of daptomycin.

Studies on the reactions between daptomycin and glyceraldehyde.

The objectives of this project were to determine the reaction pathways of daptomycin in the presence of glyceraldehyde in acidic solutions, and to quantitate the kinetics of the major pathways. In the presence of glyceraldehyde (pH range 1-7 at 25 to 60 degrees C), daptomycin formed two major products separable by RP-HPLC. The products were identified using UV spectroscopy, fluorimetry, mass spectrometry, and 2D-1H NMR. The reaction scheme involved the reversible formation of imine and anilide derivatives. Carbinolamine was believed to be a common intermediate in formation pathways of both products. The carbinolamine intermediate underwent either acid catalyzed dehydration resulting in imine formation or intramolecular hydrogen bonding and bond cleavage giving rise to anilide formation. In mild acid conditions, both products reversed to daptomycin. The reaction between daptomycin and glyceraldehyde was first-order with respect to both reactants. In a pH range of 1-7, the imine formation rate was pH dependent with a maximum rate at approximate pH values of 3-4. The observed pH dependence was consistent with the pH dependence of typical amine-aldehyde reactions.