Stability of regularly prescribed oral liquids formulated with SyrSpend® SF.

The purpose of this research was to evaluate the stability of 12 oral liquid formulations frequently compounded in hospital and community settings formulated in a specific vehicle: SyrSpend® SF. The stability of melatonin, glycopyrrolate, ciclosporin, chloral hydrate, flecainide acetate, tiagabine HCl, labetalol HCl, ciprofloxacin HCl, spironolactone/hydrochlorothiazide, hydrocortisone, itraconazole and celecoxib in SyrSpend SF PH4 (liquid) was investigated at 0, 30, 60 and 90 days and stored at both controlled room temperature and refrigerated. Itraconazole samples were also investigated at 15 and 45 days. No change in odor, color or appearance was observed in the formulations during the test period. Based on the results, a beyond-use date of 30 days can be assigned to tiagabine HCl 1.0 mg/ml in SyrSpend SF when stored at controlled room temperature, and 90 days under refrigeration, improving stability data previously published using other vehicles. A beyond-use date of 60 days can be assigned to chloral hydrate 100.0 mg/ml. In this case, stability is not enhanced by refrigeration. With the rest of the formulations, less than 10% API loss occurred over 90 days at either controlled room temperature or under refrigeration. Including for example itraconazole 20.0 mg/ml, thus providing extended stability compared to simple syrup and other oral liquid vehicles. The findings of this study show that SyrSpend SF is an appropriate suspending vehicle to be used for personalized formulations of the APIs studied here.

Characterization of the iontophoretic permselectivity properties of human and pig skin.

The objectives of this research were (a) to characterize the permselective properties of human and porcine skin and (b) to assess the validity of the latter as a model membrane in iontophoresis studies. The electroosmotic transport of [14C]mannitol was followed in vitro across human and porcine skin as a function of pH, in both "anode-to-cathode" and "cathode-to-anode" directions. At physiological pH, mannitol electrotransport dominated in the anode-to-cathode direction, clearly indicating the net negative charge and the corresponding cation-permselectivity of the skin. By lowering the pH to 3.5 the direction of electroosmosis progressively reverses, indicating that the skin is becoming net positively-charged, and thus anion-selective. The degree of permselectivity (DP) of the skin at each pH value was quantified by dividing mannitol electrotransport in the predominant direction (i.e. either anodal or cathodal) by that in the opposite sense. The net charge on the skin is zero when DP equals unity, corresponding to the isoelectric point (pI) of the membrane (approximately 4.4 for pig skin and approximately 4.8 for human skin). The consistent pIs and similar pH-dependent permselectivities observed for human and pig demonstrate that porcine skin is an appropriate model for iontophoresis studies. Finally, the characterization of the permselective properties of human skin is crucial to optimize the iontophoresis of large peptides and uncharged species, which are transported primarily by electroosmosis.

Optimizing iontophoretic drug delivery: identification and distribution of the charge-carrying species.

PURPOSE: To identify and quantify, in vitro and in vivo (in humans), the charge-carrying species during transdermal iontophoresis of lidocaine hydrochloride as a function of the concentration of drug relative to that of sodium chloride in the anodal solution. METHODS: In vitro experiments in standard diffusion cells quantified lidocaine delivery and the outward migration of chloride across the skin. Electrotransport of Na+ was inferred by difference, allowing transport numbers of the three main charge-carrying species to be deduced. In vivo, outward electrotransport of Cl- was measured and compared to the corresponding in vitro results. RESULTS: The transport number of lidocaine increased linearly with increasing mole fraction and reached 0.15-0.20 at X(L) = 1.0. In the absence of Na+, most of the charge was carried by Cl- (>80%) despite the skin retaining its net negative charge and cation permselectivity. In vivo data correlated very well with in vitro results. CONCLUSIONS: The mole faction of drug (relative to competing ions of like polarity) is the crucial determinant of the extent to which it can carry charge across the skin during iontophoresis. The outward electromigration of Cl-, in the sense opposite to drug delivery, may offer a useful means by which to optimize iontophoretic efficiency in the absence of competing cations in the anode formulation.

Contributions of electromigration and electroosmosis to iontophoretic drug delivery.

PURPOSE: To determine the electromigration and electroosmotic contributions to the iontophoretic delivery of lidocaine hydrochloride, in addition to the more-lipophilic quinine and propranolol hydrochlorides, in the presence and absence of background electrolyte. METHODS: In vitro experiments, using excised pig ear skin and both vertical and side-by-side diffusion cells, were performed as a function of drug concentration and with and without background electrolytes in the anodal formulation. Concomitantly, the contribution of electroosmosis in each experimental configuration was monitored by following the transport of the neutral, polar marker molecule, mannitol. RESULTS: Electromigration was the dominant mechanism of drug iontophoresis (typically representing approximately 90% of the total flux). In the presence of background electrolyte, lidocaine delivery increased linearly with concentration as it competed more and more effectively with Na+ to carry the charge across the skin. However, iontophoretic delivery of quinine and propranolol increased non-linearly with concentration. Without electrolytes, on the other hand, electrotransport of the three drugs was essentially independent of concentration over the range 1-100 mM. Transport efficiency of lidocaine was approximately 10%, whereas that of the more lipophilic compounds was significanly less, with the major charge carrier being Cl- moving from beneath the skin into the anodal chamber. Both quinine and propranolol induced a concentration-dependent attenuation of electroosmotic flow in the normal anode-to-cathode direction. CONCLUSION: Dissecting apart the mechanistic contributions to iontophoretic drug delivery is key to the optimization of the formulation, and to the efficient use of the drug substance.

Iontophoresis: electrorepulsion and electroosmosis.

Over the last 10-15 years, the electrical enhancement of drug delivery across the skin has undergone intense investigation. During this period, considerable amounts of experimental data have been generated, and the successful enhancement of a diverse array of molecules has been achieved. Indeed, the commercial exploitation of the method can be envisaged within the next few years. Despite this progress, however, the mechanistic understanding of iontophoresis remains a challenging scientific question that is yet to be fully resolved. The routes of permeation under the influence of an applied electrical potential, and the molecular interactions of the transporting drug with these pathways, have resisted unequivocal and unambiguous identification. Equally, the relative contributions of electrorepulsion and electroosmosis to the total iontophoretic flux have proven difficult to quantify, due to the difficulty of designing appropriate experiments. The situation is further complicated by the fact that it has now been established that certain lipophilic cations, in particular, can associate strongly with the skin during their iontophoretic delivery, thereby altering the electrical properties of the membrane, and changing the mechanism of transport. In this short communication, the roles of electrorepulsion and electroosmosis have been reconsidered from a simple theoretical point of view, and experimental approaches by which their relative importance may be estimated have been proposed and subjected to initial evaluation.

Simultaneous three color and electronic cell volume analysis with a single UV excitation source.

We have adapted an Ortho ICP-22 flow cytometer (Ortho Instruments, Westwood MA) for the simultaneous measurement of three independent fluorochromes and cell volume. This has been accomplished by the addition of a third photomultiplier tube and the development of a new electronic cell volume (ECV) flow cell. Cells are first analyzed as they pass through the 100 U ECV aperture and are then excited approximately 15 musec later by the 365 nm mercury are beam reflected by a 400 nm dicroic mirror. Independent blue, green and red signals can be associated by a delay circuit to the ECV signal from the same cell. We have developed this system as an aid in the analysis of tumor cell and macrophage heterogeneity and differentiation. The choice of stain combinations to be used is extremely flexible and permits the analysis of a wide range of enzyme activities in conjunction with DNA/RNA and phagocytic probes. Data presented indicates the value of this approach in identifying the presence of plasminogen activator-like activity in both tumor and inflammatory cells within a malignant effusion as well as the quantitative expression of a number of markers of macrophage differentiation. Although the described techniques have been developed on a mercury arc instrument, they can be used equally well with cell sorters.