International Journal of Pharmaceutics (v.264, #1-2)
TITLE PAGE(EDI BOAD) (iii).
PUBLISHER'S NOTE (v).
Mucoadhesive buccal patches of miconazole nitrate: in vitro/in vivo performance and effect of ageing by Noha A Nafee; Fatma A Ismail; Nabila A Boraie; Lobna M Mortada (1-14).
Mucoadhesive patches containing 10 mg miconazole nitrate were evaluated. The patches were prepared with ionic polymers, sodium carboxymethyl cellulose (SCMC) and chitosan, or non-ionic polymers, polyvinyl alcohol (PVA), hydroxyethyl cellulose (HEC) and hydroxypropylmethyl cellulose (HPMC). Convenient bioadhesion, acceptable elasticity, swelling and surface pH were obtained. Patches exhibited sustained release over more than 5 h and the addition of polyvinyl pyrrolidone (PVP) generally enhanced the release rate. Optimum release behaviour was shown with patches containing 10% w/v PVA and 5% w/v PVP. Study of the in vivo release from this formulation revealed uniform and effective salivary levels with adequate comfort and compliance during at least 6 h. On the contrary, in vivo release of the commercial oral gel product resulted in a burst and transient release of miconazole, which diminished sharply after the first hour of application. Storage of these patches for 6 months did not affect the elastic properties, however, enhanced release rates were observed due to marked changes in the crystal habit of the drug.
Keywords: Mucoadhesive polymers; Patches; Miconazole nitrate; In vitro and in vivo release; Ageing;
Stabilization of DNA utilizing divalent cations and alcohol by Jefferson D Knight; Roger C Adami (15-24).
A novel method for protection of DNA from high shear induced damage is presented. This method uses simple divalent cations and the lyophilizable alcohol, tert-butanol, to self-assemble DNA into condensed, shear-resistant forms. The DNA used in these studies was a 5600 BP plasmid DNA encoding a therapeutic gene. Various solvents and salts were used to identify optimal conditions to condense plasmid DNA. A stable formulation was identified with plasmid DNA condensed in a cosolvent solution containing 20% (v/v) tert-butanol and 1 mM calcium chloride. The DNA was formulated at 100 μg/ml and condensed into rod and toroidal shapes that were approximately 50–300 nm in diameter. The rods were found to be kinetically stable for greater than 24 h following their preparation. Condensation of the plasmid DNA in this manner results in nearly 100% of the plasmid DNA remaining intact after 1 min of high shear stress applied by a 50 W probe sonicator. Uncondensed control plasmid DNA is completely fragmented following 30 s of identical sonication. It is believed that condensation of DNA in this manner will permit utilization of high shear-stress inducing processing techniques, such as lyophilization or spray-drying without resulting in damage to the DNA.
Keywords: Stabilization; DNA; Solvent; Gene therapy; Ion-pair complex;
Solubilization of Fluasterone in cosolvent/cyclodextrin combinations by Yan He; Ping Li; Samuel H Yalkowsky (25-34).
The combined effect of cosolvent (methanol (MeOH), ethanol (EtOH), or n-propanol (n-PrOH)) and complexant hydroxypropyl-β-cyclodextrin (HPβCD) on the solubility of Fluasterone is evaluated and explained with a simple equation. The calculated constants in the equation not only quantitatively describe the dependence of drug solubility on cosolvent and ligand concentrations, but also explain the minima that are observed in the Fluasterone solubility versus cosolvent concentration curves at fixed HPβCD concentrations.
Keywords: Solubilization; Cosolvent; Cyclodextrin; Complexation; Mixed solvent; Fluasterone;
The effect of excipients on the stability of levothyroxine sodium pentahydrate tablets by Himanshu Patel; Apryll Stalcup; Richard Dansereau; Adel Sakr (35-43).
Levothyroxine tablets, 50 μg, have been marketed for many decades but have had numerous recalls due to degradation and failure to meet potency. These experiments were devised to study the effects of various excipients on the stability of levothyroxine sodium pentahydrate in aqueous slurries and in formulated tablets. The active alone was found to be stable in the solid state for 6 months at 40 °C/75% RH whether stored in open or closed containers, and was found to be non-hygroscopic under normal processing conditions (>30% RH). In aqueous slurries with an excipient, the stability of the active improved as the pH of the slurry was increased from pH 3 to 11. Tablets manufactured with lactose anhydrous, starch, or microcrystalline cellulose failed to meet USP assay requirements at 3 months at 40 °C/75% RH. Tablets manufactured with dibasic calcium phosphate or mannitol met USP assay requirements at 3, but not 6 months when stored at 40 °C/75% RH. Tablets manufactured with dibasic calcium phosphate and a basic pH modifier, such as sodium carbonate, sodium bicarbonate, or magnesium oxide, met the USP assay requirements at both 3 and 6 months. Thus, the use of basic pH modifiers is a potential technique for improving the stability of levothyroxine sodium pentahydrate tablets.
Keywords: Levothyroxine sodium; Tablets; Excipient; Stability; Slurries; pH modifiers;
Gelatin microparticles containing propolis obtained by spray-drying technique: preparation and characterization by M.L Bruschi; M.L.C Cardoso; M.B Lucchesi; M.P.D Gremião (45-55).
Gelatin microparticles containing propolis extractive solution (PES) were prepared by spray-drying technique. The optimization of the spray-drying operating conditions and the proportions of gelatin and mannitol were investigated. Regular particle morphology was obtained when mannitol was used, whereas mannitol absence produced a substantial number of coalesced and agglomerated microparticles. Microparticles had a mean diameter of 2.70 μm without mannitol and 2.50 μm with mannitol. The entrapment efficiency for propolis of the microparticles was upto 41% without mannitol and 39% with mannitol. The microencapsulation by spray-drying technique maintained the activity of propolis against Staphylococcus aureus. These gelatin microparticles containing propolis would be useful for developing intermediary or eventual propolis dosage form without the PES’ strong and unpleasant taste, aromatic odour, and presence of ethanol.
Keywords: Propolis; Gelatin; Spray-drying; Microparticle characterization; Optimization;
Long-term stabilization of recombinant human interferon α 2b in aqueous solution without serum albumin by Llamil Ruiz; Nuria Reyes; Ladys Duany; Abrisleyda Franco; Kethia Aroche; Eugenio Hardy Rando (57-72).
The development of parenteral solution dosage forms of interferon α 2 (rhIFN-α2) without human albumin may significantly diminish the problem of forming highly immunogenic rhIFN-α2b aggregates and the potential risk of blood-transmitted diseases caused by infectious viruses and often living pathogens that may be present in the plasma. With this purpose, we evaluated the compatibility of type I borosilicate glass vials and chlorobutyl stoppers with rhIFN-α2b in an aqueous solution. At the same time, we carried out a targeted formulation screen at 37 °C of single or combined (e.g. polysorbate 80, EDTA Na2, PEG 400) potentially stabilizing excipients. Quantified biochemical results from 12 independent batches of rhIFN-α2b in a polysorbate/benzyl alcohol-based vehicle formulated at pH 7.4 were all found within the limits established by the World Health Organization for this cytokine. Real-time storage data confirmed the excellent biochemical long-term (30 months) stability of rhIFN-α2b in this aqueous solution formulation. Analyses were performed at intervals throughout the time period using reverse-phase high-performance liquid chromatography, a sandwich-type enzyme-linked immunosorbent assay, and antiviral activity as stability-indicating assays. Furthermore, both the physical stability (color, odor, appearance, pH, and absence of particulate material) and the sterility of this formulation were maintained under the proposed shelf conditions.
Keywords: Interferon; Stability; Excipient; Formulation; Degradation pathway;
Enhanced iontophoretic delivery of buspirone hydrochloride across human skin using chemical enhancers by Victor M Meidan; Mohammad Al-Khalili; Bozena B Michniak (73-83).
Buspirone hydrochloride (BH) is a structurally and pharmacologically unique anxiolytic that is used to treat a variety of different anxiety conditions. The marketed product is named BuSpar®. The in vitro iontophoretic delivery of BH through human skin was investigated in order to evaluate the feasibility of delivering a therapeutic dose of BH by this route. We also examined the influence of co-formulations of chemical enhancers (Azone®, oleic acid, menthone, cineole, and terpineol) on BH permeation, both without iontophoresis and with iontophoresis—to look for possible synergistic effects. By applying iontophoresis at 0.5 mA/cm2, it was possible to achieve a BH steady state flux of approximately 350 μg/cm2 h, which would be therapeutically effective if clinically duplicated. Importantly, 24 h of iontophoresis at 0.5 mA/cm2 did not affect skin morphology and after the current was switched off, the skin’s permeability to BH rapidly reverted to its pre-iontophoretic level. Without iontophoreis, BH transdermal flux was significantly enhanced by the application of 2.5% (v/v) concentrations of Azone®, oleic acid, or menthone but not cineole or terpineol. Furthermore, this paper identified a synergistic transport enhancement effect developing when very low current (0.025 mA/cm2) iontophoresis was applied in conjuction with Azone® treatment.
Keywords: Iontophoresis; Transdermal; Buspirone; Terpenes; Oleic acid; Azone®;
Properties of enteric coated sodium valproate pellets by L.Diane Bruce; Hans-Ulrich Petereit; Thomas Beckert; James W McGinity (85-96).
The influence of subcoat application and micro-environmental pH on the dissolution properties of enteric coated sodium valproate pellets was investigated. The pellets were prepared by solution-layering or wet-mass extrusion-spheronization methods. In order to pass the USP enteric test, the solution-layered and wet-mass extruded pellets required 35 and 25% weight gain of Eudragit® L 30D-55, respectively. The application of a subcoat of either Methocel®-E5 (HPMC) or Opadry® AMB to the pellets resulted in a delay in sodium valproate release in 0.1N HCl. Further delay in drug release was observed when citric acid was present in a HPMC subcoat or when added to the core pellet formulation. The amount of drug released from coated pellets was a function of the level of citric acid in the pellet core or subcoat and subsequent micro-environmental pH of the pellets. Citric acid exerted a plasticizing effect on the enteric polymer film and improved film formation and polymer coalescence. When greater than 10% (w/w) citric acid was present in the pellets, a decrease in drug content was observed due to the conversion of sodium valproate to the volatile compound, valproic acid. Pellets containing less than 10% (w/w) citric acid maintained potency during processing.
Keywords: Eudragit® L 30D-55; Enteric polymer; Micro-environmental pH; Subcoat; Plasticizer; Organic acid;
Photostability of 2-hydroxymethyl-4,8-dibenzo[1,2-b:5,4-b′]dithiophene-4,8-dione (NSC 656240), a potential anticancer drug by S. Silchenko; C. Schöneich; B.J. Carlson; V.J. Stella (97-105).
Stability studies of 2-hydroxymethyl-4,8-dibenzo[1,2-b:5,4-b′]dithiophene-4,8-dione (NSC 656240, dithiophene), a poorly water-soluble (∼5 μg/ml) potential anticancer drug are reported. Dithiophene stability turned out to be very sensitive to laboratory fluorescent lighting. The rate of photodegradation of dithiophene was studied in aqueous solutions at room temperature (∼25 °C) at various pH values, in MeOH, CH3CN, DMF, DMA, and in mixed nonbuffered aqueous/organic solutions. The aqueous pH-rate profile indicated no sensitivity to changing pH values. 1 H NMR and LC/MS methods were used to characterize the degradation products. Dithiophene photodegradation in the presence of air followed an apparent autoxidation pathway with dithiophene-2-aldehyde and dithiophene-2-carboxylic acid as the major degradants. The structures were confirmed against authentic samples. Dithiophene photodegradation under anaerobic conditions followed an apparent disproportionation pathway with only one identified major product, dithiophene-2-aldehyde.
Keywords: Dithiophene; Photo-oxidation; Photodegradation; Stability;