Mustafa M.A. Elsayed

The vesicle-to-micelle transformation of phospholipid-cholate mixed aggregates: a state of the art analysis including membrane curvature effects.

We revisited the vesicle-to-micelle transformation in phosphatidylcholine-cholate mixtures paying special attention to the lipid bilayer curvature effects. For this purpose, we prepared unilamellar vesicles with different starting sizes (2r(v)=45-120nm). We then studied mixtures of the unilamellar vesicles (1-8mmol kg(-1)) and sodium cholate (0-11.75mmolkg(-1)) by static and dynamic light scattering. The transformation generally comprises at least two, largely parallel phenomena; one increases and the other decreases the average mixed aggregate size. In our view, cholate first induces bilayer fluctuations that lead to vesicle asphericity, and then to lipid bilayer poration followed by sealing/reformation (or fusion). The cholate-containing mixed bilayers, whether in vesicular or open form, project thread-like protrusions with surfactant enriched ends even before complete bilayer solubilisation. Increasing cholate concentration promotes detachment of such protrusions (i.e. mixed micelles formation), in parallel to further softening/destabilising of mixed amphipat bilayers over a broad range of concentrations. Vesicles ultimately fragment into mixed thread-like micelles. Higher cholate relative concentrations yield shorter thread-like mixed micelles. Most noteworthy, the cholate-induced bilayer fluctuations, the propensity for large aggregate formation, the transformation kinetics, and the cholate concentration ensuring complete lipid solubilisation all depend on the starting mean vesicle size. The smallest tested vesicles (2r(v)=45nm), with the highest bilayer curvature, require ~30% less cholate for complete solubilisation than the largest tested vesicles (2r(v)=120nm).

PG‐liposomes: novel lipid vesicles for skin delivery of drugs

A novel type of lipid vesicles, propylene glycol‐embodying liposomes or PG‐liposomes, composed of phospholipid, propylene glycol and water, is introduced. The new lipid vesicles were developed and investigated as carriers for skin delivery of the model drug, cinchocaine base. PG‐liposomes showed high entrapment efficiency and were stable for at least one month of storage at 5 ± 1 °C. Preliminary in‐vivo skin deposition studies, carried out using albino rabbit dorsal skin, showed that PG‐liposomes were superior to traditional liposomes, deformable liposomes and ethosomes, suggesting that PG‐liposomes, introduced in the current work, are promising carriers for skin delivery of drugs.

Development of topical therapeutics for management of onychomycosis and other nail disorders: a pharmaceutical perspective.

The human nail plate is a formidable barrier to drug permeation. Development of therapeutics for management of nail diseases thus remains a challenge. This article reviews the current knowledge and recent advances in the field of transungual drug delivery and provides guidance on development of topical/ungual therapeutics for management of nail diseases, with special emphasis on management of onychomycosis, the most common nail disease. Selection of drug candidates, drug delivery approaches, and evaluation of formulations are among the topics discussed. A comprehensive mathematical description for transungual permeation is also introduced.

Development and validation of a rapid HPLC method for the determination of ketotifen in pharmaceuticals.

ABSTRACT In the present study, a simple, sensitive, rapid, and stability-indicating high performance liquid chromatographic (HPLC) method with ultraviolet detection for the analysis of ketotifen was developed and validated. The method was applied to the determination of ketotifen in pharmaceutical formulations (tablets and syrups). The HPLC method utilized isocratic elution technique with a reversed phase C8 column, detection at 297 nm and a mixture of methanol, triethylamine phosphate buffer (pH 2.8; 0.04 M), and tetrahydrofuran (43: 55: 2, v/v/v) as mobile phase at a flow rate of 1.2 mL/min. Total analysis time was about 7 min with typical retention time of ketotifen of about 5 min. The method was validated for selectivity, linearity, accuracy, and precision following International Conference of Harmonization, 1996 (ICH) recommendations. Due to its simplicity and accuracy, the method can be used for routine quality control analysis.

Insights into the roles of carrier microstructure in adhesive/carrier-based dry powder inhalation mixtures: Carrier porosity and fine particle content.

To gain insights into complex interactions in carrier-based dry powder inhalation mixtures, we studied the relationships between the carrier microstructural characteristics and performance. We used mercury intrusion porosimetry to measure the microstructural characteristics and to also derive the air permeability of eight carriers. We evaluated the performances of inhalation mixtures of each of these carriers and fluticasone propionate after aerosolization from an Aerolizer®. We did not observe a simple relationship between the carrier total porosity and the performance. Classification of the porosity according to pore size, however, provided interesting insights. The carrier nanoporosity, which refers to pores smaller than micronized drug particles, has a positive influence on the performance. Nanopores reduce the carrier effective contact area and the magnitude of interparticulate adhesion forces in inhalation mixtures. The carrier microporosity, which refers to pores similar in size to drug particles, also has a positive influence on the performance. During mixing, micropores increase the effectiveness of frictional and press-on forces, which are responsible for breaking up of cohesive drug agglomerates and for distribution of drug particles over the carrier surface. On the other hand, the carrier macroporosity, which refers to pores larger than drug particles, apparently has a negative influence on the performance. This influence is likely mediated via the effects of macropores on the powder bed tensile strength and fluidization behavior. The air permeability better represents these effects. The inhalation mixture performance improved as the carrier air permeability decreased. Interestingly, as the carrier fine particle content increased, the carrier microporosity increased and the carrier air permeability decreased. This proposes a new mechanism for the positive effect of fine excipient materials on the performance of carrier-based inhalation mixtures. Fine excipient materials apparently adhere to the surface of coarse carrier particles creating projections and micropores, which increase the effectiveness of mixing. The data also support the mechanism of powder fluidization enforcement by fine excipient materials. The current study clearly demonstrates that the microporosity and the air permeability are key dry powder inhalation carrier performance determinants. Mercury intrusion porosimetry is a useful tool in the dry powder inhalation field; it successfully allowed resolution of carrier pores which contribute differently to the performance.

Spectrophdtometric Determination of Hydralazine Hydrochloride, Oxprenolol Hydrochloride & Chlorthalidone in Combination and for Oxprenolol Hydrochloride as Single Component Dosage Form

AbstractThree component tablet assay and single component tablet assay are presented. The first is performed for hydralazine hydrochloride, oxprenolol hydrochloride & chlorthalidone existing in a ratio 2.5: 8: 1 respectively. Hydralazine is estimated through absorbance measurements at 314 nm, D1 at 315 nm or D2-at 316 nm. Modified Vierordts method-after absorbance correction from hydralazine hydrochloride interference and also D2 methods are applied for oxprenolol hydrochloride assay. Chlorthalidone, the minor component, is assayed after its extraction using D1 or D2 measured at 282 nm & 268–284 nm respectively. For single tablet assay, oxprenolol hydrochloride is assayed using Amax at 272 nm, D1-measurement at 252–274 nm & D2-measurement at 260–278 nm. The first method is suffering from systematic error corrected by the latter two methods.

The effect of membrane softeners on rigidity of lipid vesicle bilayers: Derivation from vesicle size changes

Deformability is not just a fundamentally interesting vesicle characteristic; it is also the key determinant of vesicle ability to cross the skin barrier; i.e. skin penetrability. Development of bilayer vesicles for drug and vaccine delivery across the skin should hence involve optimization of this property, which is controllable by the concentration of bilayer softeners in or near the vesicle bilayers. To this end, we propose a simple method for quantifying the effect of bilayer softeners on deformability of bilayer vesicles. The method derives the bending rigidity of vesicle bilayers from vesicle size dependence on softener concentration. To exemplify the method, we studied mixtures of soybean phosphatidylcholine with anionic sodium deoxycholate, non-ionic polyoxyethylene (20) sorbitan oleyl ester (polysorbate 80), or non-ionic polyoxyethylene (20) oleyl ether (C18:1EO20, Brij® 98). With each of the tested bilayer softeners, the bending rigidity of the resulting mixed-amphipat vesicle bilayers decreased quasi-exponentially as the concentration of the bilayer softener increased, as one would expect on theoretical ground. The bilayer bending rigidity reached low values, near the thermal stability limit, i.e. kBT, before vesicle transformation into non-vesicular aggregates began. For a soybean phosphatidylcholine concentration of 5.0mmolkg-1, the bilayer bending rigidity reached 1.5kBT at the total deoxycholate concentration of 4.1mmolkg-1 and 3.4kBT at the total polysorbate 80 concentration of 2.0mmolkg-1. In the case of C18:1EO20, the bilayer bending rigidity reached 1.5kBT at the bilayer surface occupancy α=0.1. The dependence of vesicle size on bilayer softener concentration thus reveals vesicle transformation into different aggregate structures (such as mixed micelles with poor skin penetrability) and practically valuable information on vesicle deformability. Our results compare favorably with results of literature measurements. We provide practical guidance on using the new analytical method to optimize deformable vesicle formulations.

Modeling the performance of carrier-based dry powder inhalation formulations: Where are we, and how to get there?

ABSTRACT Development of carrier‐based dry powder inhalation formulations follows till date empirical approaches. This is mainly underlain by numerousness of interplaying determinants of performance and complexity of involved interactions. Mathematical modeling helps elucidate such interactions and aids rational development of formulations. This article provides a critical overview of attempts made to model the performance of carrier‐based dry powder inhalation formulations. The complex dependence of the performance on formulation properties is comprehensively discussed. A potential microstructure‐based model is ultimately introduced.