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Systemic administration of recombinant human interleukin-2 (rIL-2) is used for treating some patients with advanced cancer. This therapy is limited by severe adverse reactions of cardiovascular and gastrointestinal origin. The effects of rIL-2 treatment on plasma levels of some prostanoids were examined in sheep in order to elucidate the mechanism of these adverse reactions. A total of 8 adult female Suffolk sheep were used. rIL-2 (0.1 mg/kg) was infused over a 30-min period in 4 sheep. Four different sheep in the control group received an excipient, which consisted of 5% mannitol and sodium dodecyl sulfate (SDS) (187 micrograms SDS/mg rIL-2), in the same way. Plasma levels of prostaglandin (PG) F2 alpha in rIL-2-treated animals showed significant increases from 1.5 to 6 h over the excipient treated animals with a maximal increase of 138% of the pooled zero time control value (p less than or equal to 0.01) at 6 h. The pooled zero time control plasma PGF2 alpha concentration was 443.0 +/- 45.9 pg/ml. Plasma levels of 6-keto-PGF1 alpha in rIL-2-treated animals showed a significant increase (p less than or equal to 0.02) over the excipient treated animals at 0.5 h but the value was only 103% of the pooled zero time control. Plasma levels of 6-keto-PGF1 alpha in excipient-treated animals showed a maximal increase of 156% of the pooled zero time control value (55.6 +/- 8.9 pg/ml) at 5 h and it was significantly higher than the rIL-2-treated sheep.(ABSTRACT TRUNCATED AT 250 WORDS)
Dissolution rates and particle sizes of phenylbutazone solvent deposited on lactose, starch, and silicon dioxide, separately, and of norethindrone and digoxin deposited on lactose were investigated. Microparticulate dispersed drugs on the surface of excipients result when drug-to-excipient ratios are low. Fast dissolution rates are observed for such systems. This effect can be extended to higher ratios when silicon dioxide is used as the excipient. Because of adsorption, however, the release from silicon dioxide is more or less limited.
Biodegradable controlled-release microsphere systems made with the biocompatible biodegradable polyester excipient poly [DL lactide-co-glycolide] constitute an exciting new technology for drug delivery to the central nervous system (CNS). The present study describes functional observations indicating that implantation of dopamine (DA) microspheres encapsulated within two different polymer excipients into denervated-striatal tissue assures a prolonged release of the transmitter in vivo. Moreover, in this regard, the results show that there were clear cut temporal differences in the effect of the two DA microsphere formulations compared in this study, probably reflecting variations in the actual composition (i.e., lactide to glycolide ratio) of the two copolymer excipients examined. This technology has considerable potential for basic research with possible clinical application.
The bioavailability (plasma concentrations, AUC and urinary excretion) of an oral solution of rifampicin was investigated in six healthy volunteers. Simultaneous administration of PAS granules produced a significant decrease in the absorption of RMP, whereas Na-PAS tablets had no effect. This indicated that the dosage form of the granules and not PAS itself was responsible for the interaction, and that the dissolution of RMP was not involved. The interaction could be reproduced by giving dummy granules that contained the same excipients but no PAS. The disintegration and dissolution of PAS granules in vitro correlated well with the disappearance of RMP from the solution. The major excipient of the granules, bentonite (a mineral closely related to kaolin), was found to adsorb rifampicin rapidly and strongly.
The topical tolerability of the commercial preparation of 1-7 Asu-eel and salmon calcitonin with 2% ammonium glycyrrhyzinate and 0.01% benzalkonium chloride, respectively, and of their excipients mixture in solution with increasing concentrations of ammonium glycyrrhyzinate and benzalkonium chloride, respectively, were assessed by investigating their effects on the mucociliary transport velocity in the ex-vivo frog palate preparation. This preparation provides an integrated biological model readily usable in the laboratory which closely resembles human nasal mucociliary clearance mechanism and can be used for rapid testing and toxicity of agents proposed for topical administration in the upper and lower airways. Frog-Ringer control, 1-7 Asu-eel and salmon calcitonin commercial spray preparations and the excipients plus 2% ammonium glycyrrhyzinate and plus 0.01% benzalkonium chloride did not modify significantly the mucociliary transport velocity, confirming their very good tolerability on ciliated epithelium. Higher concentrations of ammonium glycyrrhyzinate (10 and 20%) caused significant slowing, on average -32 and -55%, respectively. Higher concentrations of benzalkonium chloride (0.05 and 0.1%) also caused significant slowing, on average, -43.5 and -87%, respectively.
The influence of excipients, used in tablet technology, and technological processes on cholecalciferol (1) stability was investigated. It was observed that 1 degrades in the presence of some excipients. The stability of 1 may be increased by antioxidant addition. The best stabilizing effect was achieved by a alpha-tocopherol and ascorbic acid mixture. On the basis of the achieved results, tablets with 1 were prepared. Their physical and chemical properties, the content of 1, its stability and its pharmaceutical availability were determined.
The effects of common tablet excipients on the permeation of diazepam through polydimethylsiloxane membranes and on the turnover time of goldfish were studied. The permeability coefficient decreased and the turnover time increased in the presence of talc, polysorbate 80, and, possibly, fumed silicon dioxide, but these parameters were unaffected by lactose, microcrystalline cellulose, and starch.
The simultaneous release of mixtures of noninteracting chemicals incorporated in a methyl acrylate-methyl methacrylate copolymer was studied. Different mixtures of dextrose-methapyrilene hydrochloride and sodium chloride-methapyrilene hydrochlodire in the plastic were compressed into tablets, and single-surface release was obtained in 0.N HCI at 37 degrees. The amounts of both drug and excipients released per unit surface rate constants were analysed in terms of the solubility, diffusion coefficient, concentrations of each chemical, and porosity and tortuosity of the tablets. It was concluded that for each tablet system the individual solid-liquid boundaries of the incorporated chemicals had merged together, and the release could be explained by Higuchi's square foot of time relationship.
Physicochemical factors involved in the development of a topical solution of a novel corticosteroid, tipredane (1), are described. A cosolvent system consisting of polyethylene glycol 400 (PEG 400), propylene glycol, and water was used to dissolve the concentration (0.1% w/w) of 1 required for the formulation. The solvent mixture was also nonirritating to the skin. Buffering agent, antioxidant, and metal-chelating agent were required to stabilize the drug. Solubilities of hydrophilic and lipophilic excipients were ensured by careful adjustment of their concentrations, as well as that of PEG 400. Two formulations, one containing potassium citrate and the other tromethamine as the buffering agents, were identified. Upon storage, sodium metabisulfite, an antioxidant used in the formulation, oxidized to form K2SO4 in the formulation containing potassium citrate. Potassium citrate decreased the solubility and resulted in the precipitation of K2SO4 by exerting a common ion effect. Lowering of the concentrations of potassium citrate, sodium metabisulfite, and PEG 400 ensured the solubility of K2SO4 formed. There was no such precipitation of K2SO4 in the formulation buffered with tromethamine, thus indicating that tromethamine is a good buffering agent in cosolvent systems.
Mono-, di- and triglycerides are important components of oils, fats and other natural products. Since in general fatty acids are mixtures and glycerol can be differently substituted, finger-prints of the composition are suitable for better characterization. Since capillary supercritical fluid chromatography (SFC) employing carbon dioxide as mobile phase is compatible with flame ionization detection, it is possible to analyse many solutes at trace levels. Supercritical carbon dioxide offers higher solute diffusivity compared with the inert carrier gas conventionally used in gas chromatography and has a lower viscosity than the liquid solvents used in HPLC. Thus, glycerides of fatty acids can be separated and eluted at a lower temperature and with shorter analysis time in SFC. In this study the analysis of mono-, di- and triglyceride mixtures in several pharmaceutical excipients is reported using capillary SFC. Quantitative analysis is possible on the basis of a response factor established for each analyte. The accuracy of the method and its advantages are demonstrated.
The antimicrobial interactions of 49 combinations of chlorhexidine, quaternary ammonium compounds, preservatives and excipients were evaluated by the method of Berenbaum and the checkerboard titration method, with Staphylococcus aureus CIP 53154 and Escherichia coli CIP 54127 as test strains. MIC determinations were carried out as a preliminary step, and relative growth intensity was used to describe the bacteriostatic activity of surface-active agents (Amonyl 380 BA, Amonyl 671 SB). In the study of combinations, results were interpreted with Fractional Inhibitory Concentration indexes and represented by isobolograms. A fair correlation was shown between the method of Berenbaum and the checkerboard titration method. Combinations between chlorhexidine, cetrimonium bromide and benzalkonium chloride were synergistic or additive; combinations of antiseptics and preservatives were generally not antagonistic. The methods were also well adapted to the study of interactions involving surface-active agents, a critical problem in the formulation of topical antimicrobial agents.
The proportion of microcrystalline cellulose and alginic acid present as excipients in the dry mix for an oxytetracycline dihydrate tablet formulation, prepared by a conventional wet granulation process, has been shown to influence granule formation and properties. Granule size distributions have varied widely due perhaps to variation in binder distribution. Granulating with water was equally satisfactory to granulating with a PVP solution. Slugged granules produced robust tablets, which disintegrated and dissolved rapidly.
The effect of some direct compression excipients and lubricants on the adhesion of hydroxypropyl methyl cellulose films has been examined using a specially designed tensile testing apparatus (Fisher & Rowe, 1976). The adhesion was found to be influenced by both the roughness, including microporosity, of the tablet surface and its polarity. Tablets prepared from microcrystalline cellulose showed very high adhesions despite having relatively smooth surfaces, owing to the surface being saturated with hydroxyl groups able to form hydrogen bonds with the corresponding groups on the polymer. The addition of magnesium or calcium stearate to the tablet was found to decrease the adhesion, but the addition of stearic acid caused a significant increase. The effect of lubricant concentration on the adhesion could be expressed by an equation similar to that proposed by Hofrichter & McLaren (1948) for the adhesion of vinyl chloride/vinyl acetate copolymers to regenerated cellulose.
A differential scanning calorimetry and infrared spectrophotometry study of potential interactions between oxamniquine and praziquantel, two synergistic anti-parasitic drugs, indicated that they did not interact on fusion. Mixtures of the two drugs with each of nine common pharmaceutical excipients (Ac-Di-Sol, Avicel, Crospovidone, calcium phosphate, magnesium stearate, starch, lactose, PEG 6000, stearic acid) appeared to interact only with stearic acid. These results suggested that a combination solid dosage form was feasible.
Differential scanning calorimetry (DSC), Fourier transform infra-red spectroscopy (FT-IR), HPLC and TLC were used to investigate the interactions between the mucolytic drug acetylcysteine and a number of commonly used tablet and capsule excipients. Acetylcysteine was found to be compatible with microcrystalline cellulose (Avicel PH 101), sodium carboxymethylcellulose, amorphous silicon dioxide (Aerosil), PVP, cross-linked PVP (Polyplasdone XL), corn starch, saccharose and magnesium stearate. Acetylcysteine thermal stability (onset degradation temperature) was decreased in mixtures with corn starch, magnesium stearate, saccharose and lactose. Interactions of acetylcysteine with lactose, PEG 4000 and 6000, glycine, adipic acid and saccharin sodium were found using DSC and studied in detail with FT-IR, HPLC and TLC. The results suggest that acetylcysteine in mixtures with PEG 4000, glycine or saccharin sodium is degraded during storage at conditions of high temperature and humidity.
The influence of auxiliary substances and pH on the chemical transformations of insulin in pharmaceutical formulation, including various hydrolytic and intermolecular cross-linking reactions, was studied. Bacteriostatic agents had a profound stabilizing effect--phenol > m-cresol > methylparaben--on deamidation as well as on insulin intermolecular cross-linking reactions. Of the isotonicity substances, NaCl generally had a stabilizing effect whereas glycerol and glucose led to increased chemical deterioration. Phenol and sodium chloride exerted their stabilizing effect through independent mechanisms. Zinc ions, in concentrations that promote association of insulin into hexamers, increase the stability, whereas higher zinc content had no further influence. Protamine gave rise to additional formation of covalent protamine-insulin products which increased with increasing protamine concentration. The impact of excipients on the chemical processes seems to be dictated mainly via an influence on the three-dimensional insulin structure. The effect of the physical state of the insulin on the chemical stability was also complex, suggesting an intricate dependence of intermolecular proximity of involved functional groups. At pH values below five and above eight, insulin degrades relatively fast. At acid pH, deamidation at residue A21 and covalent insulin dimerization dominates, whereas disulfide reactions leading to covalent polymerization and formation of A- and B-chains prevailed in alkaline medium. Structure-reactivity relationship is proposed to be a main determinant for the chemical transformation of insulin.